Drug eluting ocular implant

ABSTRACT

Disclosed herein are drug delivery devices and methods for the treatment of ocular disorders requiring targeted and controlled administration of a drug to an interior portion of the eye for reduction or prevention of symptoms of the disorder. The devices are capable of controlled release of one or more drugs and may also include structures which allow for treatment of increased intraocular pressure by permitting aqueous humor to flow out of the anterior chamber of the eye through the device.

RELATED CASES

This application claims the benefit of U.S. Provisional Application Ser.No. 61/417,154, filed on Nov. 24, 2011, which is incorporated in itsentirety by reference herein.

BACKGROUND Field of the Invention

This disclosure relates to implantable intraocular drug delivery devicesstructured to provide targeted and/or controlled release of a drug to adesired intraocular target tissue and methods of using such devices forthe treatment of ocular diseases and disorders. In certain embodiments,this disclosure relates to a treatment of increased intraocular pressurewherein aqueous humor is permitted to flow out of an anterior chamber ofthe eye through a surgically implanted pathway. In certain embodiments,this disclosure also relates particularly to a treatment of oculardiseases with drug delivery devices affixed to the eye, such as tofibrous tissue within the eye.

Description of the Related Art

The mammalian eye is a specialized sensory organ capable of lightreception and is able to receive visual images. The retina of the eyeconsists of photoreceptors that are sensitive to various levels oflight, interneurons that relay signals from the photoreceptors to theretinal ganglion cells, which transmit the light-induced signals to thebrain. The iris is an intraocular membrane that is involved incontrolling the amount of light reaching the retina. The iris consistsof two layers (arranged from anterior to posterior), the pigmentedfibrovascular tissue known as a stroma and pigmented epithelial cells.The stroma connects a sphincter muscle (sphincter pupillae), whichcontracts the pupil, and a set of dilator muscles (dilator pupillae)which open it. The pigmented epithelial cells block light from passingthrough the iris and thereby restrict light passage to the pupil.

Numerous pathologies can compromise or entirely eliminate anindividual's ability to perceive visual images, including trauma to theeye, infection, degeneration, vascular irregularities, and inflammatoryproblems. The central portion of the retina is known as the macula. Themacula, which is responsible for central vision, fine visualization andcolor differentiation, may be affected by age related maculardegeneration (wet or dry), diabetic macular edema, idiopathic choroidalneovascularization, or high myopia macular degeneration, among otherpathologies.

Other pathologies, such as abnormalities in intraocular pressure, canaffect vision as well. Aqueous humor is a transparent liquid that fillsat least the region between the cornea, at the front of the eye, and thelens and is responsible for producing a pressure within the ocularcavity. Normal intraocular pressure is maintained by drainage of aqueoushumor from the anterior chamber by way of a trabecular meshwork which islocated in an anterior chamber angle, lying between the iris and thecornea or by way of the “uveoscleral outflow pathway.” The “uveoscleraloutflow pathway” is the space or passageway whereby aqueous exits theeye by passing through the ciliary muscle bundles located in the angleof the anterior chamber and into the tissue planes between the choroidand the sclera, which extend posteriorly to the optic nerve. About twopercent of people in the United States have glaucoma, which is a groupof eye diseases encompassing a broad spectrum of clinical presentationsand etiologies but unified by increased intraocular pressure. Glaucomacauses pathological changes in the optic nerve, visible on the opticdisk, and it causes corresponding visual field loss, which can result inblindness if untreated. Increased intraocular pressure is the only riskfactor associated with glaucoma that can be treated, thus loweringintraocular pressure is the major treatment goal in all glaucomas, andcan be achieved by drug therapy, surgical therapy, or combinationsthereof.

Many pathologies of the eye progress due to the difficulty inadministering therapeutic agents to the eye in sufficient quantitiesand/or duration necessary to ameliorate symptoms of the pathology.Often, uptake and processing of the active drug component of thetherapeutic agent occurs prior to the drug reaching an ocular targetsite. Due to this metabolism, systemic administration may requireundesirably high concentrations of the drug to reach therapeutic levelsat an ocular target site. This can not only be impractical or expensive,but may also result in a higher incidence of side effects. Topicaladministration is potentially limited by limited diffusion across thecornea, or dilution of a topically applied drug by tear-action. Eventhose drugs that cross the cornea may be unacceptably depleted from theeye by the flow of ocular fluids and transfer into the generalcirculation. Thus, a means for ocular administration of a therapeuticagent in a controlled and targeted fashion would address the limitationsof other delivery routes.

SUMMARY

In several embodiments, there is provided a drug delivery ocular implantcomprising an elongate outer shell having a proximal end, a distal end,the outer shell being shaped to define an interior lumen with at least afirst active drug positioned within the interior lumen, wherein theouter shell comprises a first thickness and wherein the outer shellcomprises one or more regions of drug release

In several embodiments, the elongate shell is formed by extrusion. Inseveral embodiments, the elongate shell comprises a biodegradablepolymer. In several embodiments, the outer shell is permeable orsemi-permeable to the first active drug, thereby allowing at least about5% of total the elution of the first active drug to occur through theportions of the shell having the first thickness.

In several embodiments, the outer shell comprises polyurethane. Inseveral embodiments, the polyurethane comprises apolysiloxane-containing polyurethane elastomer.

In several embodiments, the regions of drug release are configured toallow a different rate of drug elution as compared to the elutionthrough the outer shell. In several embodiments, the overall rate ofelution of the first active drug out of the implant is greater in thedistal region of the implant. In several embodiments, there is a greateramount of the first active drug in the distal half of the implant ascompared to the proximal half of the implant.

In several embodiments, the one or more regions of drug release compriseone or more of regions of reduced thickness shell material, one or moreorifices passing through the outer shell, or combinations thereof. Incertain embodiments, the one or more regions of drug release compriseorifices and wherein the orifices are positioned along the long axis ofthe implant shell.

In several embodiments, the implant additionally comprises one or morecoatings that alter the rate of the first active agent elution from theimplant.

In several embodiments, at least the distal-most about 5 mm to about 10mm of the interior lumen houses the drug.

In several embodiments, the elution of the first active drug from theimplant continues for at least a period of at least one year.

In several embodiments, the first active drug is present as one or moremicro-tablets, wherein the micro-tablets have a density of about 0.7g/cc to about 1.6 g/cc, an aspect ratio of length to diameter of about2.8 to 3.6, and/or minor axis of about 0.28 to 0.31 mm and a major axisof about 0.8 to 1.1 mm. In several embodiments, the first active drug ispresent in an amount of at least 70% by weight of a total weight of theone or more micro-tablets. In several embodiments, the micro-tabletshave a surface area to volume ratio of about 13 to 17. In severalembodiments, the micro-tablets have dimensions allowing passage of themicro-tablets through a conduit having an inner diameter of about 23 to25 gauge.

In several embodiments, the micro-tablets are formed by utilizing one ormore of processes selected from the group consisting of tabletting,lyophilization, granulation (wet or dry), flaking, direct compression,molding, and extrusion. In several embodiments, the micro-tablets areconfigured to balance osmotic pressure between the interior lumen andthe ocular environment external to an implant after implantation. Infurther embodiments, the micro-tablets are optionally coated with acoating that regulates the release of the first active drug from themicro-tablet. In some embodiments, the coating is a polymeric coating.

In several embodiments, the first active drug is an anti-angiogenesisagent. In several embodiments, the first active drug is selected fromthe group consisting of angiostatin, anecortave acetate, thrombospondin,VEGF receptor tyrosine kinase inhibitors and anti-vascular endothelialgrowth factor (anti-VEGF) drugs. In several embodiments, the anti-VEGFdrugs are selected from the group consisting of ranibizumab,bevacizumab, pegaptanib, sunitinib and sorafenib. In severalembodiments, the first active drug is bevacizumab.

In several embodiments, the implants as described herein optionallyfurther comprise a lumen configured to transport ocular fluid from afirst location in an eye to one or more other locations, therebyreducing intraocular pressure.

There is also provided herein methods for treating an ocular conditionor disorder in an intraocular target tissue comprising making an openingin the temporal portion of an eye to access an anterior chamber of theeye, advancing a delivery device associated with a drug delivery ocularimplant through the opening and across the anterior chamber of the eye,inserting the drug delivery ocular implant into eye tissue, positioningthe implant such that at least one of the one or more regions of drugrelease are located proximate an intraocular target, and withdrawing thedelivery device from the eye, wherein drug elutes from the implant insufficient quantity to treat an ocular condition or disorder. In someembodiments, a therapeutic effect is achieved for a period of at leastone year.

In several embodiments, the intraocular target is in the posteriorchamber of the eye. In some embodiments, the intraocular target isselected from the group consisting of the macula, the retina, the opticnerve, the ciliary body, and the intraocular vasculature.

In several embodiments, inserting the drug delivery ocular implant intoeye tissue comprises placing at least a portion of the implant in aportion of the eye selected from the group consisting of uveoscleraloutflow pathway, suprachoroidal space, and Schlemm's canal.

There is also provided for a composition for the treatment of an oculardisorder, comprising a therapeutic agent having anti-vascularendothelial growth factor (VEGF) effects, wherein the anti-VEGF agent isformed into at least one micro-tablet. In several embodiments, theanti-VEGF agent is lyophilized prior to formation of the micro-tablets.In some embodiments, the anti-VEGF agent comprises at least 70% byweight of the total weight of each micro-tablet, and in someembodiments, each micro-tablet has a density of about 0.7 g/cc to about1.6 g/cc. In additional embodiments, each of the micro-tablets has aminor axis of about 0.28 to 0.31 mm and a major axis of about 0.8 to 1.1mm. In several embodiments, each of the micro-tablets has an aspectratio of length to diameter of about 2.8 to 3.6.

In addition, there is provided a system for administering a therapeuticagent to an damaged or diseased eye, comprising an ocular implantdelivery apparatus comprising a proximal end, a distal end, and acannula having an inner diameter of about 23 to 25 gauge, an ocularimplant comprising an elongate outer shell having a proximal end, adistal end, the outer shell being shaped to define an interior lumensuitable for receiving one or more micro-tablets and comprising at leasta first thickness and comprising one or more regions of drug release,and a therapeutic agent formed in at least one micro-tablet, the agenthaving anti-vascular endothelial growth factor (VEGF) effects. Inseveral embodiments, the anti-VEGF agent is lyophilized prior toformation of the micro-tablets. In some embodiments, the anti-VEGF agentcomprises at least 70% by weight of the total weight of eachmicro-tablet. In some embodiments, each micro-tablet has a density ofabout 0.7 g/cc to about 1.6 g/cc. In additional embodiments, themicro-tablets have an aspect ratio of length to diameter of about 2.8 to3.6.

There is additionally provided for herein methods for the intravitrealinjection of an agent for the treatment of an ocular disorder,comprising advancing to the surface of the sclera of an eye a deliveryapparatus comprising a proximal end, a distal end, and a cannula havingan inner diameter of about 23 to 25 gauge and containing one or moremicro-tablets comprising a therapeutic agent having anti-vascularendothelial growth factor (VEGF) effects, an activator that functions toexpel the contents of the cannula from the apparatus via passage throughthe proximal end, piercing the scleral surface to create a hole in thesclera, further advancing the delivery apparatus thru the hole such thatthe proximal end is within the vitreal cavity of the eye, activating theactivator to expel the anti-VEGF micro-tablets; and withdrawing theapparatus from the eye, thereby treating the disorder by the delivery ofof the anti-VEGF micro-tablets.

In several embodiments, the micro-tablets have a minor axis of about0.28 to 0.31 mm and a major axis of about 0.8 to 1.1 mm. In severalembodiments, the micro-tablets have a density of about 0.7 g/cc to about1.6 g/cc.

In several embodiments, the piercing of the sclera is performed using anapparatus having a sharpened proximal end. In several embodiments, thehole within the sclera is sufficiently small to be self-healing.

In accordance with several embodiments there is provided a drug deliveryocular implant comprising an elongate outer shell having a proximal end,and a distal end, said outer shell being shaped to define an interiorlumen, and at least a first drug positioned within said interior lumen.In certain embodiments, the outer shell comprises a substantiallyuniform first thickness, wherein said outer shell is permeable orsemi-permeable to said drug, thereby allowing at least about 5% of thetotal elution of the drug to occur through the portions of the shellhaving said first thickness, and wherein said outer shell comprises oneor more regions of drug release. In some embodiments, the one or moreregions of drug release comprise regions of greater or increased elutionor permeability to the drug than the portion of the outer shell havingthe first thickness. Such regions of increased permeability may compriseone or more of the outer shell having a reduced thickness, one or moreorifices, a different material than the remainder of the outer shelland/or other means to provide increased permeability or elution of thedrug. In other embodiments, the entirety of the elution of the drug isthrough the outer shell, the entirety of which or one or more portionsof which may be considered to be a region of drug release.

In several embodiments, there is provided a drug delivery ocular implantcomprising an elongate outer shell having a proximal end, a distal end,the outer shell being shaped to define an interior lumen, and at least afirst drug positioned within the interior lumen. The outer shellpreferably has a substantially uniform first thickness that allows about5 to 15% of the total elution of the drug to occur through the shellhaving the first thickness. The outer shell may comprise one or moreregions of drug release, wherein the regions of drug release areconfigured to allow different rates of drug elution as compared to eachother. In some embodiments, the overall rate of elution of drug out ofthe implant is optionally differential along the length of the implant.

In some embodiments, there are provided implants having regions of drugrelease that are configured or have one or more regions that allow agreater rate of drug elution as compared to the elution through otherregions of the outer shell. In some embodiments, the regions of greaterdrug release comprise one or more of regions of reduced thickness shellmaterial, one or more orifices passing through the outer shell, orcombinations thereof. In some embodiments, the outer shell optionallycomprises silicone and/or may have one or more orifices passing throughthe outer shell. In such embodiments, the orifices may be positionedalong the long axis of the implant shell or elsewhere. In otherembodiments, the outer shell optionally comprises siliconized urethaneand/or may comprise regions of reduced thickness, and may or may nothave any orifices passing through the outer shell.

In several embodiments disclosed herein, there is provided a drugdelivery ocular implant comprising an outer shell having a proximal end,a distal end, and being shaped to define an interior lumen, the outershell having a substantially uniform first thickness and having one ormore regions of a second, reduced shell thickness as compared to thefirst thickness, and a drug positioned within the interior lumen,wherein the thickness of the outer shell is inversely proportional tothe rate of drug elution through the shell. In some embodiments, theouter shell of the first thickness is substantially impermeable to thedrug. Release of the drug from the interior lumen is controlled at leastin part by the permeability of the outer shell to the drug, with regionsof reduced shell thickness having a higher rate of release.

Also provided is a drug delivery ocular implant comprising an outershell having a proximal end, a distal end, and being shaped to define aninterior lumen and having one or more partitions located within theinterior lumen thereby creating two or more sub-lumens, a drugpositioned within each sub-lumen. In some embodiments, at least aportion of the outer shell is substantially impermeable to the drug, andthe outer shell also comprises one or more regions that are morepermeable to the drug relative to the remainder of the outer shell, andwherein release of the drug from the interior lumen is controlled atleast in part by the permeability of the more permeable outer shellregions.

In several embodiments there is also provided a drug delivery ocularimplant comprising an outer shell having a proximal end, a distal end,and being shaped to define an interior lumen, a drug positioned withinthe interior lumen, wherein at least a portion of the outer shell issubstantially impermeable to the drug, and the outer shell comprises oneor more regions that are more permeable to the drug relative to theremainder of the outer shell.

In several embodiments disclosed herein, there is provided a drugdelivery ocular implant comprising an outer shell being shaped to definean interior lumen, a drug positioned within the interior lumen, whereinthe outer shell is comprises a permeable material that is capable ofconveying both a solvent and the drug through the outer shell, whereinrelease of the drug from the interior lumen is initiated by the exposureof the outer shell to a suitable solvent, such that the solvent isconveyed through the permeable material to contact the drug, whereinafter contact the solvent contacts the drug, the drug is conveyedthrough the permeable material to the exterior of the outer shell, andwherein the conveyance of the drug is controlled at least in part by thepermeability of the permeable material. The outer shell may also includeone or more regions of substantially impermeable material.

In several embodiments, there is provided a medical device for thedelivery of a therapeutic agent to a patient, comprising an devicedimensioned to be positioned at an area of a patient's body, atherapeutic agent positioned on or in at least a portion of the device,and wherein at least a portion of the device provides a physical effectuseful toward mitigation of an unwanted side effect of the therapeuticagent.

In several embodiments, there is provided a drug delivery ocular implantcomprising an outer shell that has one or more orifices therein, theshell being shaped to define an interior lumen a drug positioned withinthe interior lumen one or more coatings positioned on the interiorsurface of the shell, the outer surface of the shell, and/or partiallyor fully enveloping the drug positioned within the interior lumen.Embodiments may further comprise one or more of the following optionalfeatures: the outer shell comprises a material substantially impermeableto ocular fluids, the outer shell is substantially impermeable to thedrug, at least one of the coatings at least partially defines therelease rate of the drug, and the implant is dimensioned such that thedistal end of the implant is positioned in the suprachoroidal space andthe proximal end of the implant is positioned fully within the eye.

In several embodiments, there is provided a drug delivery ocular implantcomprising an outer shell that is optionally substantially impermeableto ocular fluids and has one or more orifices therein, the shell beingshaped to define an interior lumen, a drug positioned within theinterior lumen, one or more coatings positioned on the interior surfaceof the shell, the outer surface of the shell, and/or partially or fullyenveloping the drug positioned within the interior lumen, and whereinthe implant is dimensioned such that the drug is released to a desiredintraocular target post-implantation.

In several embodiments, there is provided a drug delivery ocular implantcomprising a flexible material compounded or coated with at least onedrug, a flexible tether, wherein the flexible material may be rolled orfolded to form a tube shape, wherein the tube shape is dimensioned to beplaced within a delivery apparatus, wherein the delivery apparatusdeploys the drug delivery ocular implant to an intraocular tissue,wherein the tube shape is released upon withdrawal of the deliveryapparatus, thereby allowing the flexible material, which may be in theform of a sheet or disc, to return substantially to its original shapeor configuration.

In several embodiments, there is provided a drug delivery ocular implantcomprising an outer shell shaped to define an interior lumen or spacewith one open end, a cap dimensioned to fit within or over the one openend and having one or more orifices therein, and a drug positionedwithin the interior lumen. One or more coatings are optionallypositioned on the interior surface of the cap, the outer surface of thecap, and/or between layers of drug positioned within the interior lumen.

Any embodiments disclosed herein may optionally further comprise alumen, opening or shunt configured to transport ocular fluid from afirst, undesired location, to one or more other locations, therebyreducing intraocular pressure.

The implants provided for herein optionally provide differential elutionalong the length of the implant and in some such embodiments, have arate of elution that is greater at the distal portion of the implant ascompared more proximal regions of the implant. Moreover, implants mayoptionally additionally comprise one or more coatings on the interiorand/or exterior of the device and/or on the drug contained therein, thatalter the rate of drug elution from the implant, the coatings optionallycovering different portions of the implant.

In several embodiments, the distal-most about 5 mm to about 10 mm of theinterior lumen houses the drug. In some embodiments, the outer shell hasa length between about 10 mm and about 20 mm, an outer diameter betweenabout 150 microns to about 500 microns, and an interior lumen diameterof about 75 microns to about 475 microns.

Some embodiments provided for herein result in elution of drug from theimplant with zero-order or pseudo zero-order kinetics.

Also provided for herein are methods for treating or preventing anocular condition in an intraocular target tissue comprising making anincision in the cornea or limbus of an eye in an advantageous position(e.g., temporal, nasal, superior, inferior, and the like), advancing adelivery device associated with a drug delivery implant according toseveral of the embodiments disclosed herein through the cornea of theeye and across the anterior chamber of the eye, inserting the drugdelivery implant into the suprachoroidal space of the eye, positioningthe implant such that the one or more regions of drug release arelocated sufficiently near the intraocular target to allow substantiallyall of the drug released from the implant to reach the intraoculartarget, and withdrawing the delivery device from the eye.

In some embodiments, the intraocular target is the posterior chamber ofthe eye, the anterior chamber of the eye, both the anterior chamber andposterior of the eye, or the macula, the retina, the optic nerve, theciliary body, and the intraocular vasculature.

In several embodiments, the drug acts on the intraocular target tissueto generate a therapeutic effect for an extended period. In oneembodiment, the drug comprises a steroid. In such embodiments, theimplant contains a total load of steroid ranging from about 10 to about1000 micrograms, steroid is released from the implant at a rate rangingfrom about 0.05 to about 10 micrograms per day and/or the steroid actson the diseased or damaged target tissue at a concentration ranging fromabout 1 to about 100 nanomolar. In some embodiments, the steroidadditionally generates side effects associated with accumulation ofphysiologic fluid, and an optional shunt transports the accumulatedfluid from the first location to the remote second location (such as,for example, from the anterior chamber to an existing physiologicaloutflow pathway, such as Schlemm's canal or the uveoscleral pathway).

Various embodiments of the implants disclosed herein may comprise one ormore of the following optional features: drug being placed near thedistal end of the shell, one or more barriers placed within the interiorlumen and proximal to the drug to limit anterior (or, in someembodiments, posterior) elution of the drug, and/or a barrier thatcomprises a one-way valve positioned to allow fluid passage through theimplant in a proximal to distal direction. In some embodiments havingone or more barriers placed within the interior lumen, the one or morebarriers facilitate the simultaneous (or sequential) elution of one ormore drugs to the anterior and/or posterior chamber for targetedeffects.

In some embodiments disclosed herein, there are provided coatings,preferably polymeric coatings, that are biodegradable. In someembodiments, two or more polymeric coatings are positioned on a surfaceof the outer shell and in some such embodiments, each coating has aunique rate of biodegradation in ocular fluid (including beingsubstantially non-biodegradable), covers a different portion of theshell including covering one or more optional orifices in the shell,and/or permits ocular fluid to contact the drug within the interiorlumen by passing through an increasing number of patent orifices in theshell over time that are created by the degradation of the coatingmaterial. In some embodiments, the coatings are optionally placed on theouter surface of the shell, positioned between the drug and the interiorsurface of outer shell, and/or positioned to envelop the drug within theinterior lumen. The drug may be in the form of one or more pellets,beads, or tablets.

In several embodiments, biodegradation of the barriers or coatings istriggered by an externally originating stimulus, such as, for example,intraocular injection of a fluid that initiates biodegradation of thebarrier, application of heat, ultrasound, and radio frequency, and thelike. In some embodiments, the barriers and/or coatings degrade fasterthan the drug, while in other embodiments, the degradation rate of thedrug is faster, or in still other embodiments, in which the rate ofdegradation is unique for each.

Any of the embodiments disclosed herein optionally further comprise oneor more anchor structures, one or more excipients compounded with thedrug, one or more orifices or openings in the proximal portion of thedevice to allow drainage of ocular fluid from the anterior chamber ofthe eye, and/or one or more wicks passing through any outer shell of theimplant.

Several embodiments optionally comprise a retention protrusionconfigured to anchor the implant to an ocular tissue. Such retentionprotrusions optionally comprise one or more of ridges, claws, threads,flexible ribs, rivet-like shapes, flexible barbs, barbed tips, expandingmaterial (such as a hydrogel), and biocompatible adhesives. In someembodiments, the expanding material is placed on an exterior surface ofthe outer shell of the implant and expands after contact with a solvent,such as, for example, intraocular fluid.

Implants provided for herein are optionally anchored (e.g., anymechanism or element that allows an implant to become affixed to,secured to or otherwise attached, either permanently or transiently, toa suitable target intraocular tissue) to a intraocular tissue, such asciliary muscles, the ciliary tendons, the ciliary fibrous band, thetrabecular meshwork, the iris, the iris root, the lens cortex, the lensepithelium, to or within the lens capsule, the sclera, the scleral spur,the choroid, or to or within Schlemm's canal. In certain embodimentscomprising an implant anchored within the lens capsule, such an implantis preferably implanted concurrently, or after, removal of the nativelens (e.g., by cataract surgery).

In some embodiments, the devices comprise one or more regions that arepermeable to a drug or more permeable to a drug than other regions of adevice. The increased permeability may be achieved by any means,including, but not limited to: use of thinner or decreased thickness ofmaterial that has some degree of permeability to the drug, whereby thedecreased thickness increases the rate of diffusion or transport of thedrug; orifices or holes wherein the orifices or holes may be of anysuitable size or shape to allow egress of drug and/or ingress of ocularfluids; use of a second material that has increased permeability of adrug; use of a coating which enhances transport of a drug from theinterior of a device to the exterior; and any combination of theforegoing.

Any of the implant embodiments described herein may also furthercomprise a lumen or passageway to allow drainage of ocular fluid fromfirst location to a second location, such as, for example, from theanterior chamber of the eye to a physiological outflow pathway.

In any of the embodiments disclosed herein, the drug preferably isreleased from the implant to act on a diseased or damaged target tissueto generate a therapeutic effect. In some embodiments, the drugadditionally generates side effects associated with accumulation ofphysiologic fluid and in such embodiments the implant may furthercomprise a stent or passage to transport the accumulated fluid from thefirst location to the remote second location.

According the disclosure herein, any of the implants described maycomprise a shell of metal or polymeric material, which includeshomopolymers, polymer blends and copolymers, such as random copolymersand block copolymers. In some embodiments, the polymeric materialcomprises ethyl vinyl acetate, polyethylene, Elastane™, silicone,polyurethane, and/or polyamide.

In those embodiments having regions of reduced shell thickness, suchregions may be created by any suitable means, including one or more ofablation, stretching, etching, grinding, and molding. The region may bein any pattern on or around the implant, including a spiral pattern,patches, rings and/or bands.

Regions that are characterized by having an increased rate of drugdelivery, be it by reduced shell thickness, orifices, permeable materialor any other means or combination of means described herein may bepresent at or in any portion or combination of portions of the device.Preferably the regions are placed so as to direct the drug to tissues inthe eye which are the target of treatment by the drug. In someembodiments, such regions (or a single such region) are preferablyconcentrated towards the distal end of an elongate device so as totarget delivery of a drug to tissues in the distal portions of theposterior chamber of the eye.

Implants as described herein may optionally be configured to interactwith a recharging device in order to recharge the implant with anadditional or supplementary dose of the drug. Such rechargeableimplants, optionally comprise a reversible coupling between the proximalend of the implant and a clamping sleeve on the recharging device. Incertain embodiments, the clamping sleeve houses flexible clampinggrippers that create a secure coupling between the implant and therecharging device. The secure coupling optionally enables the rechargingdevice to enable a flexible pusher or filling tube incorporated into therecharging device to be used to deliver a drug to a lumen of theimplant. In several embodiments, the secure coupling between the implantand the recharging device enable a spring loaded flexible pusher tubeincorporated into the recharging device to be used to deliver drug to alumen of the implant. In some embodiments, there is a provided a one-waypassage that allows deposition of a drug to the lumen of the implant,but prevents the drug from escaping the lumen through the passage afterthe removal of the recharging device.

In some embodiments, implants are provided that further comprise atleast one partition within the interior lumen, thereby creating at leasttwo sub-lumens. In some embodiments having two or more sub-lumens, eachsub-lumen optionally houses a different drug or a differentconcentration of the same drug as compared to the other sub-lumens,optionally releases a drug to a different portion of the eye. In someembodiments where the implant houses multiple drugs one drug istherapeutically effective against an ocular disorder and another drugameliorates a side effect of administration of the first drug.

In addition to sub-lumens, several embodiments are provided for in whichimplants further comprise: distal regions of the shell that are morepermeable to the drugs as compared to more proximal regions; havepartitions that are positioned perpendicular to a long axis of the outershell; have partitions that are semi-permeable to a drug positionedwithin the sub-lumens; and/or wherein drug release from the sub-lumensoccurs first from the distal-most sub-lumen and last from theproximal-most sub-lumen.

In some such embodiments, the partitions are optionally varied inpermeability to the drugs within the sub-lumens such that the overallelution profile includes periods of time where drug release is reducedor eliminated.

Any of the embodiments disclosed herein comprising a lumen, pathway orshunt in addition to drug elution in an implant may optionally drainfluid to any existing physiological outflow pathway, including thesuprachoroidal space, the trabecular meshwork, or Schlemm's canal, andmay optionally target drug delivery to the anterior chamber of the eye,the posterior chamber of the eye, both the anterior chamber andposterior of the eye, and/or specifically target the macula, the retina,the optic nerve, the ciliary body, and/or the intraocular vasculature.

Any of the embodiments disclosed herein may deliver a drug and/orprovide a therapeutic effect for several days, one to two months, atleast six months, at least a year, at least two years, at least threeyears, at least four years, and/or at least five years.

Any of the embodiments disclosed herein may be configured to target adiseased or damaged target tissue that is characterized by a limitedability to swell without loss or impairment of physiological function.

In several embodiments, there is provided a method of treating orpreventing an ocular condition comprising: making an incision in theeye, inserting a drug delivery implant according to several embodimentsdisclosed herein into the suprachoroidal space of the eye, andwithdrawing the delivery device from the eye.

In some embodiments, the implants are positioned such that the regionsof the implant from which drug is released are located sufficiently nearan intraocular target to allow substantially all of the drug releasedfrom the implant to reach the intraocular target

In several embodiments, the methods disclosed herein optionally compriseone or more of making an incision in the cornea or limbus of the eye inan advantageous position (e.g., temporal, nasal, superior, inferior, andthe like), advancing the delivery device through the cornea of the eyeand to the site of implantation.

In several embodiments there is provided a method for delivering anocular implant comprising a stent according to several embodimentsdisclosed herein that simultaneously treats an ocular condition andlimits treatment-associated side-effects, particularly those associatedwith increased fluid accumulation in the eye and/or increasedintraocular pressure.

Other embodiments optionally comprise placing a peripheral iridotomyadjacent to the implanted drug delivery device and optionallymaintaining the peripheral iridotomy as patent with a stent.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features, aspects, and advantages of the presentdisclosure will now be described with reference to the drawings ofembodiments, which embodiments are intended to illustrate and not tolimit the disclosure. One of ordinary skill in the art would readilyappreciated that the features depicted in the illustrative embodimentsare capable of combination in manners that are not explicitly depicted,but are both envisioned and disclosed herein.

FIG. 1 illustrates a schematic cross sectional view of an eye.

FIG. 2 illustrates a drug delivery device in accordance with embodimentsdisclosed herein.

FIGS. 3A and 3B illustrate drug delivery devices in accordance withembodiments disclosed herein.

FIG. 4 illustrates a drug delivery device in accordance with embodimentsdisclosed herein.

FIG. 5 illustrates a drug delivery device in accordance with embodimentsdisclosed herein.

FIGS. 6A-6I illustrate various aspects of a drug delivery device inaccordance with embodiments disclosed herein.

FIG. 7 illustrates a cross sectional view of drug delivery implant inaccordance with embodiments disclosed herein.

FIG. 8 illustrates the distal portion of a drug delivery implant inaccordance with embodiments disclosed herein.

FIG. 9 illustrates the distal portion of another drug delivery implantin accordance with embodiments disclosed herein.

FIGS. 10A-10G illustrate other drug delivery implants in accordance withembodiments disclosed herein.

FIGS. 11A-11B illustrate various embodiments of implants as disclosedherein that house one or more drug-containing pellets within theimplant.

FIG. 12 illustrates another drug delivery implant incorporating a shuntin accordance with embodiments disclosed herein.

FIGS. 13A-13C illustrate drug delivery implants in accordance withembodiments disclosed herein.

FIG. 14 illustrates a drug delivery implant in accordance withembodiments disclosed herein.

FIG. 15 illustrates an illustrative embodiment of a drug deliveryimplant and retention protrusion.

FIG. 16 illustrates an embodiment of a drug delivery implant inaccordance with embodiments disclosed herein.

FIG. 17 illustrates another embodiment of a drug delivery implant inaccordance with embodiments disclosed herein.

FIGS. 18A-18Q illustrate various drug delivery devices in accordancewith embodiments disclosed herein.

FIGS. 19A-19Y illustrate various anchor elements used in severalembodiments disclosed herein.

FIGS. 20A-20C illustrates a rechargeable drug delivery device inaccordance with embodiments disclosed herein.

FIG. 21 illustrates an apparatus for implanting a drug delivery inaccordance with embodiments disclosed herein.

FIG. 22 illustrates another apparatus for implanting a drug deliverydevice in accordance with embodiments disclosed herein.

FIG. 23 illustrates a schematic cross-sectional view of an eye with adelivery device containing an implant being advanced across the anteriorchamber. The size of the implant is exaggerated for illustrationpurposes.

FIG. 24 illustrates an additional implantation procedure according toseveral embodiments disclosed herein. The size of the implant isexaggerated for illustration purposes.

FIG. 25 illustrates a schematic cross-sectional view of an eye with adelivery device being advanced adjacent the anterior chamber angle. Thesize of the implant is exaggerated for illustration purposes.

FIG. 26 illustrates a schematic cross-section view of an eye with adelivery device implanting an implant that extends from the anteriorchamber through the suprachoroidal space and terminates in closeproximity to the macula.

FIGS. 27A-27D illustrate a cross-sectional view an eye during the stepsof one embodiment of a method for implanting drug delivery devices asdisclosed herein.

FIG. 28 illustrates a schematic cross-sectional view of an eye with adelivery device being advanced across the eye targeting the irisadjacent to the anterior chamber angle. The size of the shunt isexaggerated for illustration purposes.

FIG. 29 illustrates a schematic cross-sectional view of an eye withanother embodiment of a delivery device targeting the iris adjacent tothe anterior chamber angle. The size of the shunt is exaggerated forillustration purposes.

FIG. 30 illustrates a schematic cross-section view of an eye with animplant anchored to the iris.

FIG. 31 illustrates a schematic cross-section view of an eye with animplant implanted in the anterior chamber angle.

DETAILED DESCRIPTION

Achieving local ocular administration of a drug may require directinjection or application, but could also include the use of a drugeluting implant, a portion of which, could be positioned in closeproximity to the target site of action within the eye or within thechamber of the eye where the target site is located (e.g., anteriorchamber, posterior chamber, or both simultaneously). Use of a drugeluting implant could also allow the targeted delivery of a drug to aspecific ocular tissue, such as, for example, the macula, the retina,the ciliary body, the optic nerve, or the vascular supply to certainregions of the eye. Use of a drug eluting implant could also provide theopportunity to administer a controlled amount of drug for a desiredamount of time, depending on the pathology. For instance, somepathologies may require drugs to be released at a constant rate for justa few days, others may require drug release at a constant rate for up toseveral months, still others may need periodic or varied release ratesover time, and even others may require periods of no release (e.g., a“drug holiday”). Further, implants may serve additional functions oncethe delivery of the drug is complete. Implants may maintain the patencyof a fluid flow passageway within an ocular cavity, they may function asa reservoir for future administration of the same or a differenttherapeutic agent, or may also function to maintain the patency of afluid flow pathway or passageway from a first location to a secondlocation, e.g. function as a stent. Conversely, should a drug berequired only acutely, an implant may also be made completelybiodegradable.

Implants according to the embodiments disclosed herein preferably do notrequire an osmotic or ionic gradient to release the drug(s), areimplanted with a device that minimizes trauma to the healthy tissues ofthe eye which thereby reduces ocular morbidity, and/or may be used todeliver one or more drugs in a targeted and controlled release fashionto treat multiple ocular pathologies or a single pathology and itssymptoms. However, in certain embodiments, an osmotic or ionic gradientis used to initiate, control (in whole or in part), or adjust therelease of a drug (or drugs) from an implant. In some embodiments,osmotic pressure is balanced between the interior portion(s) of theimplant and the ocular fluid, resulting in no appreciable gradient(either osmotic or ionic). In such embodiments, variable amounts ofsolute are added to the drug within the device in order to balance thepressures.

As used herein, “drug” refers generally to one or more drugs that may beadministered alone, in combination and/or compounded with one or morepharmaceutically acceptable excipients (e.g. binders, disintegrants,fillers, diluents, lubricants, drug release control polymers or otheragents, etc.), auxiliary agents or compounds as may be housed within theimplants as described herein. The term “drug” is a broad term that maybe used interchangeably with “therapeutic agent” and “pharmaceutical” or“pharmacological agent” and includes not only so-called small moleculedrugs, but also macromolecular drugs, and biologics, including but notlimited to proteins, nucleic acids, antibodies and the like, regardlessof whether such drug is natural, synthetic, or recombinant. Drug mayrefer to the drug alone or in combination with the excipients describedabove. “Drug” may also refer to an active drug itself or a prodrug orsalt of an active drug.

As used herein, “patient” shall be given its ordinary meaning and shallalso refer to mammals generally. The term “mammal”, in turn, includes,but is not limited to, humans, dogs, cats, rabbits, rodents, swine,ovine, and primates, among others. Additionally, throughout thespecification ranges of values are given along with lists of values fora particular parameter. In these instances, it should be noted that suchdisclosure includes not only the values listed, but also ranges ofvalues that include whole and fractional values between any two of thelisted values.

In several embodiments, a biocompatible drug delivery ocular implant isprovided that comprises an outer shell that is shaped to define at leastone interior lumen that houses a drug for release into an ocular space.The outer shell is polymeric in some embodiments, and in certainembodiments is substantially uniform in thickness, with the exception ofareas of reduced thickness, through which the drug more readily passesfrom the interior lumen to the target tissue. In other words, a regionof drug release may be created by virtue of the reduced thickness. Inseveral other embodiments the shell of the implant comprises one or moreregions of increased drug permeability (e.g., based on the differentialcharacteristics of portions of the shell such as materials, orifices,etc.), thereby creating defined regions from which the drug ispreferentially released. In other embodiments, if the material of theouter shell is substantially permeable to a drug, the entire outer shellcan be a region of drug release. In yet another embodiment, portions ofthe outer shell that surround where the drug is placed in the interiorlumen or void of the device may be considered a region of drug release.For example, if the drug is loaded toward the distal end or in thedistal portion of the device (e.g. the distal half or distal ⅔ of thedevice), the distal portion of the device will be a region of drugrelease as the drug will likely elute preferentially through thoseportions of the outer shell that are proximate to the drug. Therefore,as used herein, the term “region of drug release” shall be given itsordinary meaning and shall include the embodiments disclosed in thisparagraph, including a region of drug permeability or increased drugpermeability based on the characteristics of a material and/or thethickness of the material, one or more orifices or other passagewaysthrough the implant (also as described below), regions of the deviceproximate to the drug and/or any of these features in conjunction withone or more added layers of material that are used to control release ofthe drug from the implant. Depending on the context, these terms andphrases may be used interchangeably or explicitly throughout the presentdisclosure.

In some embodiments, the outer shell comprises one or more orifices toallow ocular fluid to contact the drug within the lumen (or lumens) ofthe implant and result in drug release. In some embodiments, asdiscussed in more detail below, a layer or layers of a permeable orsemi-permeable material is used to cover the implant (wholly orpartially) and the orifice(s) (wholly or partially), thereby allowingcontrol of the rate of drug release from the implant. Additionally, insome embodiments, combinations of one or more orifices, a layer orlayers covering the one or more orifices, and areas of reducedthicknesses are used to tailor the rate of drug release from theimplant.

In still other embodiments, combinations of materials may be used toconstruct the implant (e.g., polymeric portions of outer shell bonded orotherwise connected, coupled, or attached to outer shell comprising adifferent material).

In still other embodiments, the drug to be delivered is not containedwithin an outer shell. In several embodiments, the drug is formulated asa compressed pellet (or other form) that is exposed to the environmentin which the implant is deployed. For example, a compressed pellet ofdrug is coupled to an implant body which is then inserted into an ocularspace (see e.g., FIG. 19T). In some embodiments, the implant bodycomprises a fluid flow pathway. In some embodiments, the implantoptionally comprises a retention feature. In some embodiments, the drugis encapsulated, coated, or otherwise covered with a biodegradablecoating, such that the timing of initial release of the drug iscontrolled by the rate of biodegradation of the coating. In someembodiments, such implants are advantageous because they allow avariable amount of drug to be introduced (e.g., not constrained bydimensions of an implant shell) depending on the type and duration oftherapy to be administered. In some embodiments having a shunt feature(shown generally in FIG. 19T) the shunt feature works in conjunctionwith the drug to treat one or more symptoms of the disease or conditionaffecting the patient. For example, in some embodiments, the shuntremoves fluid from the anterior chamber while the drug simultaneouslyreduces the production of ocular fluid. In other embodiments, asdiscussed herein, the shunt counteracts one or more side effects ofadministration of a particular drug (e.g., the shunt drains ocular fluidthat was produced by the actions of the drug).

In some embodiments, biocompatible drug delivery implants comprise aflexible sheet or disc flexibly optionally associated with (e.g.,tethered to) a retention protrusion (e.g., an anchoring element,gripper, claw, or other mechanism to permanently or transiently affixthe sheet or disc to an intraocular tissue). In certain of suchembodiments, the therapeutic agent is compounded with the sheet or discand/or coated onto the sheet or disc. In some embodiments, the flexiblesheet or disc implants are dimensioned such that they may be rolled orfolded to be positioned within the lumen of a delivery instrument, forexample a small diameter hollow needle.

Following implantation at the desired site within the eye, drug isreleased from the implant in a targeted and controlled fashion, based onthe design of the various aspects of the implant, preferably for anextended period of time. The implant and associated methods disclosedherein may be used in the treatment of pathologies requiring drugadministration to the posterior chamber of the eye, the anterior chamberof the eye, or to specific tissues within the eye, such as the macula,the ciliary body or other ocular target tissues.

FIG. 1 illustrates the anatomy of an eye, which includes the sclera 11,which joins the cornea 12 at the limbus 21, the iris 13 and the anteriorchamber 20 between the iris 13 and the cornea 12. The eye also includesthe lens 26 disposed behind the iris 13, the ciliary body 16 andSchlemm's canal 22. The eye also includes a uveoscleral outflow pathway,which functions to remove a portion of fluid from the anterior chamber,and a suprachoroidal space positioned between the choroid 28 and thesclera 11. The eye also includes the posterior region 30 of the eyewhich includes the macula 32.

GENERAL

In some embodiments functioning as a drug delivery device alone, theimplant is configured to deliver one or more drugs to anterior region ofthe eye in a controlled fashion while in other embodiments the implantis configured to deliver one or more drugs to the posterior region ofthe eye in a controlled fashion. In still other embodiments, the implantis configured to simultaneously deliver drugs to both the anterior andposterior region of the eye in a controlled fashion. In yet otherembodiments, the configuration of the implant is such that drug isreleased in a targeted fashion to a particular intraocular tissue, forexample, the macula or the ciliary body. In certain embodiments, theimplant delivers drug to the ciliary processes and/or the posteriorchamber. In certain other embodiments, the implant delivers drug to oneor more of the ciliary muscles and/or tendons (or the fibrous band). Insome embodiments, implants deliver drug to one or more of Schlemm'scanal, the trabecular meshwork, the episcleral veins, the lens cortex,the lens epithelium, the lens capsule, the sclera, the scleral spur, thechoroid, the suprachoroidal space, retinal arteries and veins, the opticdisc, the central retinal vein, the optic nerve, the macula, the fovea,and/or the retina. In still other embodiments, the delivery of drug fromthe implant is directed to an ocular chamber generally. It will beappreciated that each of the embodiments described herein may target oneor more of these regions, and may also optionally be combined with ashunt feature (described below).

In several embodiments, the implant comprises an outer shell. In someembodiments, the outer shell is tubular and/or elongate, while in otherembodiments, other shapes (e.g., round, oval, cylindrical, etc.) areused. In certain embodiments, the outer shell is not biodegradable,while in others, the shell is optionally biodegradable. In severalembodiments, the shell is formed to have at least a first interiorlumen. In certain embodiments, the first interior lumen is positioned ator near the distal end of the device. In other embodiments, a lumen mayrun the entire length of the outer shell. In some embodiments, the lumenis subdivided. In certain embodiments, the first interior lumen ispositioned at or near the proximal end of the device. In thoseembodiments additionally functioning as a shunt, the shell may have oneor more additional lumens within the portion of the device functioningas a shunt.

In several embodiments, the drug (or drugs) is positioned within theinterior lumen (or lumens) of the implant shell. In several embodiments,the drug is preferentially positioned within the more distal portion ofthe lumen. In some embodiments, the distal-most 15 mm of the implantlumen (or lumens) house the drug (or drugs) to be released. In someembodiments, the distal-most 10 mm, including 1, 2, 3, 4, 5, 6, 7, 8,and 9 mm of the interior lumen(s) house the drug to be released.

In some embodiments, the drug diffuses through the shell and into theintraocular environment. In several embodiments, the outer shellmaterial is permeable or semi-permeable to the drug (or drugs)positioned within the interior lumen, and therefore, at least someportion of the total elution of the drug occurs through the shellitself, in addition to that occurring through any regions of increasedpermeability, reduced thickness, orifices etc. In some embodiments,about 1% to about 50% of the elution of the drug occurs through theshell itself. In some embodiments, about 10% to about 40%, or about 20%to about 30% of the elution of the drug occurs through the shell itself.In some embodiments, about 5% to about 15%, about 10% to about 25%,about 15% to about 30%, about 20% to about 35%, about 25% to about 40%,about 30% to about 45%, or about 35% to about 50% of the elution of thedrug occurs through the shell itself. In certain embodiments, about 1%to 15%, including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14% ofthe total elution of the drug (or drugs) occurs through the shell. Theterm “permeable” and related terms (e.g. “impermeable” or “semipermeable”) are used herein to refer to a material being permeable tosome degree (or not permeable) to one or more drugs or therapeuticagents and/or ocular fluids. The term “impermeable” does not necessarilymean that there is no elution or transmission of a drug through amaterial, instead such elution or other transmission is negligible orvery slight, e.g. less than about 3% of the total amount, including lessthan about 2% and less than about 1%.

In some embodiments, the implant shell has one or more regions ofincreased drug permeability through which the drug is released to thetarget ocular tissue in a controlled fashion.

In some embodiments, the drug or drugs are positioned within theinterior lumen or lumens of an implant wherein the implant shellcomprises one or more orifices to allow ocular fluid to contact theagent or agents and result in drug release. In some embodiments, theimplant comprises a polymeric coating on the exterior surface of ashell. In other embodiments, the implant comprises a polymeric coatingon the interior surface of a shell. In still other embodiments,polymeric coatings are on both the interior and exterior surfaces. Inyet other embodiments, the polymeric coatings are biodegradable. Someembodiments comprise a non-polymeric coating (e.g. heparin) in place of,or in addition to the polymeric coatings. Additionally, in someembodiments, combinations of one or more orifices, a layer or layerscovering the one or more orifices, and areas of reduced thicknesses areused to tailor the rate of drug release from the implant.

In some embodiments, the interior lumen containing the drug(s) areseparated from the proximal portion of the implant by way of an proximalbarrier within the interior lumen that prevents elution of the drug tothe anterior portion of the eye. In some embodiments, the interiorlumen(s) containing the drug(s) are separated from the proximal portionof the implant by way of a one way valve within the interior lumen thatprevents elution of the drug to the anterior portion of the eye, butallows ocular fluid from the anterior portion of the eye to reach theinterior lumen(s) containing the drug(s).

In some embodiments, the implant further comprises a proximal portionstructured for recharging/refilling the implant with the same, or anadditional therapeutic drug, multiple drugs, or adjuvant compound, orcompounds.

In some embodiments comprising a shunt, the shunt portion, followingimplantation at an implantation site, drains fluid from an ocularchamber into a physiologic outflow space to reduce intraocular pressure.In some embodiments, the implant is dimensioned such that when eitherthe proximal or distal end of the implant is at an implantation sitenear a tissue targeted for drug delivery, the outflow ports of theimplant will drain ocular fluid to a remote region and/or aphysiological outflow pathway.

For example, in some embodiments, the implant is dimensioned such that,following implantation, the distal end of the implant is locatedsufficiently close to the macula that the drug delivered by the implantreaches the macula. In some embodiments incorporating a shunt feature,the implant is dimensioned such that when the distal end of the implantis positioned sufficiently near the macula, the proximal end of theimplant extends into the anterior chamber of the eye. In thoseembodiments, outflow ports in the implant, described in more detailbelow, are positioned such that the aqueous humor will be drained intothe uveoscleral outflow pathway or other physiological outflow pathway.

In still other embodiments, combination drug delivery-shunt implants maybe positioned in any physiological location that necessitatessimultaneous dug delivery and transport of fluid from a firstphysiologic site to a second site (which may be physiologic or externalto a patient). In some embodiments, the shunt feature works inconjunction with the drug delivery function to potentiate thetherapeutic effects of the delivered agent. In other embodiments, thetherapeutic effects of the delivered agent may be associated withunwanted side effects, such as fluid accumulation or swelling. In someembodiments, the shunt feature functions ameliorate the side effects ofthe delivered agent. It shall be appreciated that the dimensions andfeatures of the implants disclosed herein may be tailored to attaintargeted and/or controlled delivery to various regions of the eye whilestill allowing communication with a physiological outflow pathway.

The delivery instruments, described in more detail below, may be used tofacilitate delivery and/or implantation of the drug delivery implant tothe desired location of the eye. The delivery instrument may be used toplace the implant into a desired position, such as the inferior portionof the iris, the suprachoroidal space near the macula, or otherintraocular region, by application of a continual implantation force, bytapping the implant into place using a distal portion of the deliveryinstrument, or by a combination of these methods. The design of thedelivery instruments may take into account, for example, the angle ofimplantation and the location of the implant relative to an incision.For example, in some embodiments, the delivery instrument may have afixed geometry, be shape-set, or actuated. In some embodiments, thedelivery instrument may have adjunctive or ancillary functions, such asfor example, injection of dye and/or viscoelastic fluid, dissection, oruse as a guidewire. As used herein, the term “incision” shall be givenits ordinary meaning and may also refer to a cut, opening, slit, notch,puncture or the like.

In certain embodiments the drug delivery implant may contain one or moredrugs which may or may not be compounded with a bioerodible polymer or abioerodible polymer and at least one additional agent. In still otherembodiments, the drug delivery implant is used to sequentially delivermultiple drugs. Additionally, certain embodiments are constructed usingdifferent outer shell materials, and/or materials of varied permeabilityto generate a tailored drug elution profile. Certain embodiments areconstructed using different numbers, dimensions and/or locations oforifices in the implant shell to generate a tailored drug elutionprofile. Certain embodiments are constructed using different polymercoatings and different coating locations on the implant to generate atailored drug elution profile. Some embodiments elute drug at a constantrate, others yield a zero-order release profile. Yet other embodimentsyield variable elution profiles. Still other embodiments are designed tostop elution completely or nearly completely for a predetermined periodof time (e.g., a “drug holiday”) and later resume elution at the same ora different elution rate or elution concentration. Some such embodimentselute the same therapeutic agent before and after the drug holiday whileother embodiments elute different therapeutic agents before and afterthe drug holiday.

Drug Delivery Implants

The present disclosure relates to ophthalmic drug delivery implantswhich, following implantation at an implantation site, providecontrolled release of one or more drugs to a desired target regionwithin the eye, the controlled release being for an extended, period oftime. Various embodiments of the implants are shown in FIGS. 2-20 andwill be referred to herein.

FIG. 2 depicts a cross sectional schematic of one embodiment of animplant in accordance with the description herein. The implant comprisesan outer shell 54 made of one or more biocompatible materials. The outershell of the implant is manufactured by extrusion, drawing, injectionmolding, sintering, micro machining, laser machining, and/or electricaldischarge machining, or any combination thereof. Other suitablemanufacturing and assembly methods known in the art may also be used. Inseveral embodiments, the outer shell is tubular in shape, and comprisesat least one interior lumen 58. In some embodiments the interior lumenis defined by the outer shell and a partition 64. In some embodiments,the partition is impermeable, while in other embodiments the partitionis permeable or semi-permeable. In some embodiments, the partitionallows for the recharging of the implant with a new dose of drug(s). Insome other embodiments, other shell shapes are used, yet still produceat least one interior lumen. In several embodiments the outer shell ofthe implant 54 is manufactured such that the implant has a distalportion 50 and a proximal portion 52. In several embodiments, thethickness of the outer shell 54 is substantially uniform. In otherembodiments the thickness varies in certain regions of the shell.Depending on the desired site of implantation within the eye, thickerregions of the outer shell 54 are positioned where needed to maintainthe structural integrity of the implant.

In some embodiments, the implant is made of a flexible material. Inother embodiments, a portion of the implant is made from flexiblematerial while another portion of the implant is made from rigidmaterial. In some embodiments, the implant comprises one or moreflexures (e.g., hinges). In some embodiments, the drug delivery implantis pre-flexed, yet flexible enough to be contained within the straightlumen of a delivery device.

In other embodiments, at least a portion of the implant (e.g., aninternal spine or an anchor) is made of a material capable of shapememory. A material capable of shape memory may be compressed and, uponrelease, may expand axially or radially, or both axially and radially,to assume a particular shape. In some embodiments, at least a portion ofthe implant has a preformed shape. In other embodiments, at least aportion of the implant is made of a superelastic material. In someembodiments, at least a portion of the implant is made up of nitinol. Inother embodiments, at least a portion of the implant is made of adeformable material.

In several embodiments the majority of the surface of the outer shell ofthe implant is substantially impermeable to ocular fluids. In severalembodiments, the majority of the surface of the outer shell of theimplant is also substantially impermeable to the drug 62 housed withinthe interior lumen of the implant (discussed below). In otherembodiments, the outer shell is semi-permeable to drug and/or ocularfluid and certain regions of the implant are made less or more permeableby way of coatings or layers or impermeable (or less permeable) materialplaced within or on the outer shell.

In several embodiments, the outer shell also has one or more regions ofdrug release 56. In some embodiments the regions of drug release are ofreduced thickness compared to the adjacent and surrounding thickness ofthe outer shell. In some embodiments, the regions of reduced thicknessare formed by one or more of ablation, stretching, etching, grinding,molding and other similar techniques that remove material from the outershell. In other embodiments the regions of drug release are of adifferent thickness (e.g., some embodiments are thinner and otherembodiments are thicker) as compared to the surrounding outer shell, butare manufactured with an increased permeability to one or more of thedrug 62 and ocular fluid. In still other embodiments, the outer shell isuniform or substantially uniform in thickness but constructed withmaterials that vary in permeability to ocular fluid and drugs within thelumen. As such, these embodiments have defined regions of drug releasefrom the implant.

The regions of drug release may be of any shape needed to accomplishsufficient delivery of the drug to a particular target tissue of theeye. For example, in FIG. 2, the regions 56 are depicted as definedareas of thinner material. FIG. 3A depicts the regions of drug releaseused in other embodiments, namely a spiral shape of reduced thickness56. In some embodiments, the spiral is located substantially at thedistal end of the implant, while in other embodiments, the spiral mayrun the length of the interior lumen. In still other embodiments, thespiral region of drug release is located on the proximal portion of theimplant. In some embodiments, the spiral is on the interior of theimplant shell (i.e., the shell is rifled; see FIG. 3A). In otherembodiments, spiral is on the exterior of the shell (see FIG. 3B). Inother embodiments, the region of drug release is shaped ascircumferential bands around the implant shell.

FIG. 4 depicts another embodiment, wherein a region of drug release islocated at the distal-most portion of the implant. Certain suchembodiments are used when more posterior regions of the eye are to betreated. Alternatively, or in conjunction with the embodiment of FIG. 4,the proximal portion of the implant may also have a region of drugrelease at or near the proximal most portion. In other embodiments, theregions of drug release are uniformly or substantially uniformlydistributed along the distal and/or proximal portions of the implant. Insome embodiments, the regions of drug release are located at or near thedistal end of the implant. In certain embodiments, the implants (basedon the regions of drug release (based on thickness/permeability,orifices, layers etc.) are strategically placed to create a differentialpattern of drug elution from the implant, depending on the target tissueto be treated after implantation. In some embodiments, the regions ofdrug release are configured to preferentially elute drug from the distalend of the implant. In some such embodiments, the regions of drugrelease are strategically located at or near a target tissue in the moreposterior region of the eye after the implantation procedure iscomplete. As discussed in more detail below, in several embodiments, theregions of drug release comprises one (or more) orifices that allowcommunication between an interior lumen of the implant and theenvironment in which the implant is implanted. It shall also beappreciated from the disclosure herein that, in certain embodiments,combinations of regions of drug release (as described above) may becombined with one or more orifices and/or coatings (below) in order totailor the drug release profile.

In several embodiments, lumens are present in both the proximal anddistal portions of the implant (see FIG. 5; 58 a and 58, respectively).In such embodiments both the proximal 52 and the distal portion 50 ofthe implant have one or more regions of drug release. In some suchembodiments the proximal and distal portions of the implant house twodifferent drugs 62 a (proximal) and 62 (distal) in the lumens. See FIG.5. In other embodiments, the proximal and distal portion of the implantmay house the same drugs, or the same drug at different concentrationsor combined with alternate excipients. It will be appreciated that theplacement of the regions of drug release, whether within the proximalportion, distal portion, or both portions of the implant, are useful tospecifically target certain intraocular tissues. For example, placementof the region of drug release at the distal most portion of the implant,is useful, in some embodiments, for specifically targeting drug releaseto particular intraocular regions, such as the macula. In otherembodiments, the regions of drug release are placed to specificallyrelease drug to other target tissues, such as the ciliary body, theretina, the vasculature of the eye, or any of the ocular targetsdiscussed above or known in the art. In some embodiments, the specifictargeting of tissue by way of specific placement of the region of drugrelease reduces the amount of drug needed to achieve a therapeuticeffect. In some embodiments, the specific targeting of tissue by way ofspecific placement of the region of drug release reduces non-specificside effects of an eluted drug. In some embodiments, the specifictargeting of tissue by way of specific placement of the region of drugrelease increases the overall potential duration of drug delivery fromthe implant.

Regardless of their shape and location(s) on the outer shell of the inimplant, the regions of drug release are of a defined and known area.The defined area assists in calculating the rate of drug elution fromthe implant (described below). The regions of drug release are formed inseveral embodiments by reducing the thickness of the outer shell incertain defined areas and/or controlling the permeability of a certainregion of the outer shell. FIGS. 6A-1 represent certain embodiments ofthe region of drug release. FIGS. 6A and B depict overlapping regions ofa thicker 54 and thinner 54 a portion of the outer shell material withthe resulting formation of an effectively thinner region of material,the region of drug release 56. FIGS. 6C and 6D depict joinder of thicker54 with thinner 54 a portions of the outer shell material. The resultingthinner region of material is the region of drug release 56. It will beappreciated that the joining of the thicker and thinner regions may beaccomplished by, for example, butt-welding, gluing or otherwise adheringwith a biocompatible adhesive, casting the shell as a single unit withvarying thickness, heat welding, heat fusing, fusing by compression, orfusing the regions by a combination of heat and pressure. Other suitablejoining methods known in the art may also be used.

FIG. 6E depicts a thicker sleeve of outer shell material overlapping atleast in part with a thinner shell material. The thinner, non-overlappedarea, 56, is the region of drug release. It will be appreciated that thedegree of overlap of the material is controllable such that the regionof non-overlapped shell is of a desired area for a desired elutionprofile.

FIG. 6F illustrates an outer shell material with a thin area 56 formedby one or more of ablation, stretching, etching, grinding, molding andother similar techniques that remove material from the outer shell.

FIG. 6G depicts a “tube within a tube” design, wherein a tube with afirst thickness 54 is encased in a second tube with a second thickness54 a. The first tube has one or more breaks or gaps in the shell, suchthat the overlaid thinner shell 54 a covers the break or gap, therebyforming the region of drug release. In the embodiment shown in FIG. 6G,and in certain other embodiments, the break or gap in the shell with afirst thickness 54, does not communicate directly with the externalenvironment.

FIG. 6H depicts an embodiment wherein the region of drug release isbordered both by the outer shell 54 and by a substantially impermeablematrix material 55 having a communicating particulate matter 57dispersed within the impermeable matrix. In several embodiments, thecommunicating particulate matter is compounded with the impermeablematrix material during implant manufacturing. The implant may then becontacted with a solvent, which is subsequently carried through thecommunicating particulate matter and reaches the drug housed within thelumen of the implant. Preferred solvents include water, saline, orocular fluid, or biocompatible solvents that would not affect thestructure or permeability characteristics of the impermeable matrix.

As the drug in the lumen is dissolved into the solvent, it travelsthrough the communicating particulate matter from the lumen of theimplant to the ocular target tissue. In some embodiments, the implant isexposed to a solvent prior to implantation in the eye, such that drug isready for immediate release during or soon after implantation. In otherembodiments, the implant is exposed only to ocular fluid, such thatthere is a short period of no drug release from the implant while theocular fluid moves through the communicating particulate matter into thelumen of the implant.

In some such embodiments, the communicating particulate matter compriseshydrogel particles, for example, polyacrylamide, cross-linked polymers,poly2-hydroxyethylmethacrylate (HEMA) polyethylene oxide, polyAMPS andpolyvinylpyrrolidone, or naturally derived hydrogels such as agarose,methylcellulose, hyaluronan. Other hydrogels known in the art may alsobe used. In some embodiments, the impermeable material is silicone. Inother embodiments, the impermeable material may be Teflon®, flexiblegraphite, silicone rubber, silicone rubber with fiberglassreinforcement, Neoprene®, fiberglass, cloth inserted rubber, vinyl,nitrile, butyl, natural gum rubber, urethane, carbon fiber,fluoroelastomer, and or other such impermeable or substantiallyimpermeable materials known in the art. In this and other embodimentsdisclosed herein, terms like “substantially impermeable” or“impermeable” should be interpreted as relating to a material's relativeimpermeability with regard to the drug of interest. This is because thepermeability of a material to a particular drug depends uponcharacteristics of the material (e.g. crystallinity, hydrophilicity,hydrophobicity, water content, porosity) and also to characteristics ofthe drug.

FIG. 6I depicts another embodiment wherein the region of drug release isbordered both by the outer shell 54 and by an impermeable matrixmaterial 55, such as silicone having a communicating particulate matter57 dispersed within the impermeable matrix. In other embodiments, theimpermeable material may be Teflon®, flexible graphite,polydimethylsiloxane and other silicone elastomers, Neoprene@,fiberglass, cloth inserted rubber, vinyl, nitrile, butyl, natural gumrubber, urethane, carbon fiber, fluoroelastomer, and or other suchimpermeable or substantially impermeable materials known in the art. Inseveral embodiments, the communicating particulate matter is compoundedwith the impermeable matrix material during implant manufacturing. Theresultant matrix is impermeable until placed in a solvent that causesthe communicating particulate matter to dissolve. In severalembodiments, the communicating particles are salt crystals (for example,sodium bicarbonate crystals or sodium chloride crystals). In otherembodiments, other soluble and biocompatible materials may be used asthe communicating particulate matter. Preferred communicatingparticulate matter is soluble in a solvent such as water, saline, ocularfluid, or another biocompatible solvent that would not affect thestructure or permeability characteristics of the impermeable matrix. Itwill be appreciated that certain embodiments, the impermeable matrixmaterial compounded with a communicating particulate matter hassufficient structural integrity to form the outer shell of the implant(i.e., no additional shell material is necessary).

In certain embodiments, the communicating particles are extracted with asolvent prior to implantation. The extraction of the communicatingparticles thus creates a communicating passageway within the impermeablematerial. Pores (or other passages) in the impermeable material allowocular fluid to pass into the particles, which communicate the fluidinto the lumen of implant. Likewise, the particles communicate the drugout of the lumen of the implant and into the target ocular tissue.

In contrast to a traditional pore or orifice (described in more detailbelow), embodiments such as those depicted in FIGS. 6H and 6Icommunicate drug from the lumen of the implant to the ocular tissuethrough the communicating particles or through the resultant vacancy inthe impermeable matrix after dissolution of the particle. Theseembodiments therefore create an indirect passage from the lumen of theimplant to the eye (i.e. a circuitous route or tortuous path ofpassage). Thus, purposeful design of the particulate material, its rateof communication of fluids or rate of dissolution in solvent, allowsfurther control of the rate and kinetics of drug release.

In several embodiments, the region of drug release comprises one or moreorifices. It shall be appreciated that certain embodiments utilizeregions of drug release that are not orifices, either alone or incombination with one or more orifices in order to achieve a controlledand targeted drug release profile that is appropriate for the envisionedtherapy. FIG. 7 shows a cross sectional schematic of one embodiment ofan implant in accordance with the description herein. As discussedabove, the implant comprises a distal portion 50, a proximal portion 52,an outer shell 54 made of one or more biocompatible materials, and oneor more orifices that pass through the shell 56 a. In some embodimentsthe outer shell of the implant is substantially impermeable to ocularfluids. In several embodiments, the implant houses a drug 62 within theinterior lumen 58 of the implant.

As discussed in more detail below, in some embodiments, the drugcomprises a therapeutically effective drug against a particular ocularpathology as well as any additional compounds needed to prepare thetherapeutic agent in a form with which the drug is compatible. In someembodiments the therapeutic agent is in the form of a drug-containingpellet. Some embodiments of therapeutic agent comprise a drug compoundedwith a polymer formulation. In certain embodiments, the polymerformulation comprises a poly (lactic-co-glycolic acid) or PLGAco-polymer or other biodegradable or bioerodible polymer. While the drugis represented as being placed within the lumen 58 in FIG. 7, it hasbeen omitted from several other Figures, so as to allow clarity of otherfeatures of those embodiments. It should be understood, however, thatall embodiments herein optionally include one or more drugs.

In several embodiments, the implant further comprises a coating 60 whichmay be positioned in various locations in or on the implant as describedbelow. In some embodiments, the coating 60 is a polymeric coating. FIG.8 depicts an implant wherein the coating 60 is positioned inside theimplant, but enveloping the therapeutic agent housed within the lumen,while FIG. 9 depicts the coating 60 on the exterior of the shell 54.Some other embodiments may comprise implants with non-polymeric coatingsin place of, or in addition to a polymeric coating. The coating isoptionally biodegradable. Some other embodiments may comprise an implantmade entirely of a biodegradable material, such that the entire implantis degraded over time. In some embodiments, the coating is placed overthe entire implant (e.g., enveloping the implant) while in otherembodiments only a portion of the implant is covered. In someembodiments, the coating is on the exterior surface of the implant. Insome embodiments, the coating is placed on the luminal wall within theimplant. Similarly, in some embodiments in which the coating ispositioned inside the implant, the coating covers the entire innersurface of the lumen, while in other embodiments, only a portion of theinner surface is covered. It shall be appreciated that, in addition tothe regions of drug release described above, implants according toseveral embodiments, disclosed herein combine regions of drug releasewith one or more coatings in order to control drug releasecharacteristics.

In several embodiments, one or more orifices 56 a traversing thethickness of the outer shell 54 provide communication passages betweenthe environment outside the implant and the interior lumen 58 of theimplant (FIGS. 7-9). The one or more orifices are created through theimplant shell by way of drilling through the various shells of aparticular implant or any other technique known in the art. The orificesmay be of any shape, such as spherical, cubical, ellipsoid, and thelike. The number, location, size, and shape of the orifices created in agiven implant determine the ratio of orifice to implant surface area.This ratio may be varied depending on the desired release profile of thedrug to be delivered by a particular embodiment of the implant, asdescribed below. In some embodiments, the orifice to implant surfacearea ratio is greater than about 1:100. In some embodiments, the orificeto implant surface area ratio ranges from about 1:10 to about 1:50, fromabout 1:30 to about 1:90, from about 1:20 to about 1:70, from about 1:30to about 1:60, from about 1:40 to about 1:50. In some embodiments, theorifice to implant surface area ratio ranges from about 1:60 top about1:100, including about 1:70, 1:80 and 1:90.

In other embodiments, the outer shell may contain one or more orifice(s)56 b in the distal tip of the implant, as shown in FIGS. 10A and 10B.The shape and size of the orifice(s) can be selected based on thedesired elution profile. Still other embodiments comprise a combinationof a distal orifice and multiple orifices placed more proximally on theouter shell. Additional embodiments comprise combinations of distalorifices, proximal orifices on the outer shell and/or regions of drugrelease as described above (and optionally one or more coatings).Additional embodiments have a closed distal end. In such embodiment theregions of drug release (based on thickness/permeability of the shell,orifices, coatings, placement of the drug, etc.) are arranged along thelong axis of the implant. Such a configuration is advantageous in orderto reduce the amount of tissue damage caused by the advancing distal endthat occurs during the several embodiments of the implantationprocedures disclosed herein.

In some embodiments, the distal orifice comprises a biodegradable orbioerodible plug 61 with a plurality of orifice(s) 56 b that maintaindrug elution from the implant, should one or more orifices becomeplugged with tissue during the insertion/implantation. In otherembodiments, the orifice(s) can comprise permeable or semi-permeablemembranes, porous films or sheets, or the like. In some suchembodiments, the permeable or semi-permeable membranes, films, or sheetsmay lie outside the shell and cover the orifices, inside the shell tocover the orifices or both. The permeability of the material willpartially define the release rate of the drug from the implant, which isdescribed in further detail below. Such membranes, sheets, or films areuseful in those embodiments having elongated orifices in the outershell. Arrows in FIG. 10B depict flow of drug out of the implant.

In several embodiments, an additional structure or structures within theinterior of the lumen partially controls the elution of the drug fromthe implant. In some embodiments, a proximal barrier 64 a is positionedproximally relative to the drug 62 (FIGS. 7 and 10C). An optional shuntfeature may also be included which comprises outflow apertures 66 incommunication with a proximal inflow lumen 68 located in the proximalregion 52 of the implant. In addition to the layer or layers ofpermeable or semi-permeable material may be used to envelope the drugdiscussed above, FIG. 10C depicts an internal plug 210 that is belocated between the drug 62 and the various orifices 56 a and 56 b incertain embodiments. In such embodiments, the internal plug need notcompletely surround the drug. In some embodiments, the material of theinternal plug 210 differs from that of the shell 54, while in someembodiments the material of the internal plug 210 is the same materialas that of the shell 54. Suitable materials for the internal pluginclude, but are not limited to, agarose or hydrogels such aspolyacrylamide, polymethyl methacrylate, or HEMA (hydroxyethylmethacrylate). In additional any material disclosed herein for use inthe shell or other portion of the implant may be suitable for theinternal plug, in certain embodiments.

In such embodiments where the material is the same, the physicalcharacteristics of the material used to construct 210 are optionallydifferent than that of the shell 54. For example, the size, density,porosity, or permeability of the material of 210 may differ from that ofthe shell 54. In some embodiments, the internal plug is formed in place(i.e. within the interior lumen of the implant), for example bypolymerization, molding, or solidification in situ of a dispensedliquid, powder, or gel. In other embodiments, the internal plug ispreformed external to the shell placed within the shell prior toimplantation. In such embodiments, tailored implants are constructed inthat the selection of a pre-formed internal plug may be optimized basedon a particular drug, patient, implant, or disease to be treated. Inseveral embodiments, the internal plug is biodegradable or bioerodible,while in some other embodiments, the internal plug is durable (e.g., notbiodegradable or bioerodible).

In several embodiments, the internal plug may be closely fit or bondedto the inner wall of shell. In such embodiments, the internal plug ispreferably permeable to the drug, thereby allowing passage of the drugthrough the plug, through the orifices and to the target tissue. In someembodiments, the internal plug is also permeable to body fluids, suchthat fluids from outside the implant may reach the drug. The overallrelease rate of drug from the device in this case may be controlled bythe physical characteristics of several aspects of the implantcomponents, including, but not limited to, the area and volume of theorifices, the surface area of any regions of drug release, the size andposition of the internal plug with respect to both the drug and theorifices and/or regions of drug release, and the permeability of theinternal plug to the drug and bodily fluids. In addition, in severalembodiments, the internal plug increases path length between the drugand the orifices and/or regions of drug release, thereby providing anadditional point of control for the release rate of drug.

In several other embodiments, the internal plug 210 may be more looselyfit into the interior lumen of the shell which may allow flow ortransport of the drug around the plug. See FIG. 10D. In still otherembodiments, the internal plug may comprise two or more pieces orfragments. See FIG. 10E. In such embodiments with a looser fitting orfragmented plug, the drug may elute from the implant by passing throughthe gap between the internal plug and the interior wall of shell. Thedrug may also elute from the implant by passing through the gaps betweenpieces or fragments of the internal plug. The drug may also elute fromthe implant by passing through the permeable inner plug. Similarly,bodily fluids may pass from the external portion of the implant into theimplant and reach the drug by any of these, or other, pathways. It shallbe appreciated that elution of the drug can occur as a result of acombination of any of these routes of passage or permeability.

In several embodiments, the orifices 56 a are covered (wholly orpartially) with one or more elution membranes 100 that provide a barrierto the release of drug 62 from the interior lumen 58 of the implantshell 54. See FIG. 10F. In several embodiments, the elution membrane ispermeable to the therapeutic agent, to bodily fluids or to both. In someembodiments the membrane is elastomeric and comprises silicone. In otherembodiments, the membrane is fully or partially coated with abiodegradable or bioerodible material, allowing for control of theinception of entry of bodily fluid, or egress of therapeutic agent fromthe implant. In certain embodiments, the membrane is impregnated withadditional agents that are advantageous, for example an anti-fibroticagent, a vasodilator, an anti-thrombotic agent, or a permeabilitycontrol agent. In addition, in certain embodiments, the membranecomprises one or more layers 100 a, 100 b, and 100 c in FIG. 100, forexample, allowing a specific permeability to be developed.

Similar to the internal plug and regions of drug release describedabove, the characteristics of the elution membrane at least partiallydefine the release rate of the therapeutic agent from the implant. Thus,the overall release rate of drug from the implant may be controlled bythe physical characteristics of the implant, including, but not limitedto, the area and volume of the orifices, the surface area of any regionsof drug release, the size and position of any internal plug with respectto both the drug and the orifices and/or regions of drug release, andthe permeability of any layers overlaying any orifices or regions ofdrug release to the drug and bodily fluids.

In some embodiments, multiple pellets 62 of single or multiple drug(s)are placed end to end within the interior lumen of the implant (FIG.11A). In some such embodiments, the orifices 56 a (or regions of drugrelease) are positioned at a more distal location on the implant shell.In other such embodiments, the orifices 56 a (or regions of drugrelease) are positioned at a more proximal location on the implantshell, depending on the ocular tissue being targeted. In some otherembodiments a partition 64 is employed to seal therapeutic agents fromone another when contained within the same implant inner lumen. In someembodiments, the partition 64 bioerodes at a specified rate. In someembodiments, the partition 64 is incorporated into the drug pellet andcreates a seal against the inner dimension of the shell of the implant54 in order to prevent drug elution in an unwanted direction. In certainembodiments further comprising a shunt, a partition may be positioneddistal to the shunt outlet holes, which are described in more detailbelow.

In certain alternative embodiments, the orifices or regions of drugrelease may be positioned along a portion of or substantially the entirelength of the outer shell that surrounds the interior lumen and one ormore partitions may separate the drugs to be delivered.

An additional non-limiting additional embodiment of a drugpellet-containing implant is shown in FIG. 11B (in cross section). Incertain embodiments, the pellets are micro-pellets 62′ (e.g.,micro-tablets) with characteristics described more fully below. In someembodiments, such one or more such micro-pellets are housed within apolymer tube having walls 54′ of a desired thickness. In someembodiments, the polymer tube is extruded and optionally has a circularcross-section. In other embodiments, other shapes (e.g., oval,rectangular, octagonal etc.) are formed. In some embodiments, thepolymer is a biodegradable polymer, such as those discussed more fullybelow. Regardless of the material or the shape, several embodiments ofthe implant are dimensioned for implantation into the eye of a subject(e.g., sized to pass through a 21 gauge, 23 gauge, 25 gauge, 27 gauge,or smaller needle).

Within that context, the dimensions of several embodiments of such adevice may be varied in order to provide a desired release time for thetherapeutic agent in the micro-pellets. For example, the wall thicknessof a polymer tube can be adjusted to alter the permeability of thepolymer tube to the therapeutic agent. Moreover, in the case ofbiodegradable polymers, the wall thickness can also be altered in orderto control the overall rate of degradation of the device. In combinationwith other variables more fully described herein, e.g., the polymerchemistry and the molecular weight of the polymers used, elution of thetherapeutic agent from the implant is highly controllable.

As shown generally in FIG. 11B, the micro-pellet 62′ can be housedwithin a compartment defined by endpieces or partitions 64′. In someembodiments, the endpieces 64′ defining each lumen or compartment arethermoformed from the same material as tubing 54′. In other embodiments,they may be formed of sections of polymer filaments. In still otherembodiments, the endpieces are formed within the interior of the tube byinjecting or otherwise applying small volumes of thermosetting polymers,adhesives, polymer solutions in volatile solvents, and the like.Alternatively, endpieces may be machined from hard polymers, metals orother materials, and positioned and retained within the tube usingsolvent or adhesive bonding. In those embodiments wherein the endpiecesare polymers, some embodiments employ biodegradable polymers, which maybe designed to degrade before, at the time of, or after themicro-pelleted therapeutic agent is released. Moreover, polymericendpieces may comprise the same polymer as the extruded polymeric tube54′, or may be a different polymer.

While shown in FIG. 11B as dimensioned to hold one micro-tablet oftherapeutic agent 62′, it shall be appreciated that, in someembodiments, the lumen 58′ may be dimensioned to hold a plurality ofmicro-tablets comprising the same or differing therapeutic agents.Advantageously, such embodiments employed an extruded shell and one ormore micro-pellets allow the release of the therapeutic agents from theimplant, in a controlled fashion, without the therapeutic agent beingexposed to the elevated temperatures that are often required forextrusion. Rather, the shell may first be extruded and then loaded withmicro-pellets once temperatures are normalized.

As discussed in more detail herein, each tablet comprises a therapeuticagent (also referred to herein as an active pharmaceutical ingredient(API)) optionally combined with one or more excipients. Excipients mayinclude, among others, freely water soluble small molecules (e.g.,salts) in order to create an osmotic pressure gradient across the wallof tubing 54′. In some embodiments, such a gradient increases stress onthe wall, and decreases the time to release drug.

The in vivo environment into which several embodiments of the implantsdisclosed herein are positions may be comprised of a water-basedsolution (such as aqueous humor or blood plasma) or gel (such asvitreous humor). Water from the surrounding in vivo environment may, insome embodiments, diffuse through semipermeable or fenestrated stentwalls into the drug reservoir (e.g., one or more of the interior lumens,depending on the embodiment). Water collecting within thedrug-containing interior lumen then begins dissolving a small amount ofthe tablet or drug-excipient powder. The dissolution process continuesuntil a solution is formed within the lumen that is in osmoticequilibrium with the in vivo environment.

In additional embodiments, osmotic agents such as saccharides or saltsare added to the drug to facilitate ingress of water and formation ofthe isosmotic solution. With relatively insoluble drugs, for examplecorticosteroids, the isosmotic solution may become saturated withrespect to the drug in certain embodiments. In certain such embodiments,saturation can be maintained until the drug supply is almost exhausted.In several embodiments, maintaining a saturated condition isparticularly advantageous because the elution rate will tend to beessentially constant, according to Fick's Law.

Implants such as those depicted generally in FIG. 11B may be implantedsingularly (e.g., a single implant) or optionally as a plurality ofmultiple devices. In some embodiments, the plurality of implants may bejoined together (e.g., end to end) to form a single, larger implant. Asdiscussed above, and in greater detail below, such implants may begenerated having different drug release times, for example, by varyingthe time or—degradation properties of extruded tubing 54′. Implantationof a plurality of varied devices having different release times, adesired overall drug release profile can be obtained based on the serial(or concurrent) release of drug from the plurality of implants a giventime period. For example, release times can be designed such that afirst period of drug release occurs, and is then followed by a drug“holiday” prior a second period of drug release.

Several embodiments of the implant may also comprise a shunt in additionto functioning as a drug delivery device. The term “shunt” as usedherein is a broad term, and is to be given its ordinary and customarymeaning to a person of ordinary skill in the art (and it is not to belimited to a special or customized meaning), and refers withoutlimitation to the portion of the implant defining one or more fluidpassages for transport of fluid from a first, often undesired location,to one or more other locations. In some embodiments, the shunt can beconfigured to provide a fluid flow path for draining aqueous humor fromthe anterior chamber of an eye to an outflow pathway to reduceintraocular pressure, such as is depicted generally in FIG. 12. In otherembodiments the shunt can be configured to provide a fluid flow path fordraining aqueous humor to an outflow pathway. Still other embodimentscan be configured to drain ocular fluid or interstitial fluid from thearea in and around the eye to a remote location. Yet other combinationdrug delivery-shunt implants may be configured to drain physiologicalfluid from a first physiologic site to a second site (which may bephysiologic or external to a patient). In still additional embodiments,the shunt additionally (or alternatively) functions to provide a bulkfluid environment to facilitate the dilution and/or elution of the drug.

The shunt portion of the implant can have an inflow portion 68 and oneor more outflow portions 66. As described above, the outflow portion maybe disposed at or near the proximal end 52 of the implant. While notillustrated, in some embodiments a shunt outflow portion may be disposedat or near the distal end of the implant with the inflow portionresiding a different location (or locations) on the implant. In someembodiments, when the implant is deployed, the inflow portion may besized and configured to reside in the anterior chamber of the eye andthe outflow portion may be sized and configured to reside in thesupraciliary or suprachoroidal space. In some embodiments, the outflowportion may be sized and configured to reside in the supraciliary regionof the uveoscleral outflow pathway, the suprachoroidal space, other partof the eye, or within other physiological spaces amenable to fluiddeposition.

In some embodiments, at least one lumen extends through the shuntportion of the implant. In some embodiments, there is at least one lumenthat operates to conduct the fluid through the shunt portion of theimplant. In certain embodiments, each lumen extends from an inflow endto an outflow end along a lumen axis. In some embodiments the lumenextends substantially through the longitudinal center of the shunt. Inother embodiments, the lumen can be offset from the longitudinal centerof the shunt.

In implants additionally comprising a shunt in the proximal portion ofthe device, the first (most proximal) outflow orifice on the implant ispositioned between 1 and 10 mm from the anterior chamber of the subject.In some embodiments additionally comprising a shunt in the proximalportion of the device, the first (most proximal) outflow orifice on theimplant is positioned preferably between 2 and 5 mm from the anteriorchamber of the subject. Additional outflow orifices may be positioned inmore distal locations, up to or beyond the point where the interiorlumen housing the drug or therapeutic agent begins.

In some embodiments, the implant is formed with one or more dividerspositioned longitudinally within the outer shell, creating multipleadditional sub-lumens within the interior lumen of the shell. Thedivider(s) can be of any shape (e.g. rectangular, cylindrical) or sizethat fits within the implant so as to form two or more sub-lumens, andmay be made of the same material or a different material than the outershell, including one or more polymers, copolymers, metal, orcombinations thereof. In one embodiment, a divider is made from abiodegradable or bioerodible material. The multiple sub-lumens may be inany configuration with respect to one another. In some embodiments, asingle divider may used to form two sub-lumens within the implant shell.See e.g., FIG. 13A. In some embodiments, the two sub-lumens are of equaldimension. In other embodiments the divider may be used to createsub-lumens that are of non-equivalent dimensions. In still otherembodiments, multiple dividers may be used to create two or moresub-lumens within the interior of the shell. In some embodiments thelumens may be of equal dimension. See, e.g. FIG. 13B. Alternatively, thedividers may be positioned such that the sub-lumens are not ofequivalent dimension.

In some embodiments, one or more of the sub-lumens formed by thedividers may traverse the entire length of the implant. In someembodiments, one or more of the sub-lumens may be defined of blocked offby a transversely, or diagonally placed divider or partition. Theblocked off sub-lumens may be formed with any dimensions as required toaccommodate a particular dose or concentration of drug.

In other embodiments, the implant is formed as a combination of one ormore tubular shell structures 54 that are substantially impermeable toocular fluids that are nested within one another to form a “tube withina tube” design, as shown in FIG. 13C. In alternative embodiments, acylindrical divider is used to partition the interior of the implantinto nested “tubes.” In such embodiments, a coating 60, which canoptionally be polymer based, can be located in or on the tubularimplant. In such embodiments, at least a first interior lumen 58 isformed as well as an ocular fluid flow lumen 70. In some embodiments,the ocular fluid flow lumen 70 is centrally located. In otherembodiments, it may be biased to be located more closely to the implantshell. In still other embodiments, additional shell structures are addedto create additional lumens within the implant. Drugs 62 may bepositioned within one or more of said created lumens. Orifices orregions of drug release may be placed as necessary to allow ocular fluidto contact the therapeutic agent. In certain embodiments the coating isplaced on the outer surface of the outer shell. In certain embodiments,two or more biodegradable coatings are used on a single implant, witheach coating covering a separate or overlapping portion of the implant.In those embodiments employing biodegradable coatings, each coatingoptionally has a unique rate of biodegradation in ocular fluid.

In some embodiments, a wick 82 is included in the implant (FIG. 14). Thewick may take any form that assists in transporting ocular fluid fromthe external side of the device to an interior lumen more rapidly thanwould be achieved through the orifices of regions of drug release alone.While FIG. 14 depicts a wick passing through an orifice, it shall beappreciated that an implant having only regions of drug release are alsocapable of employing a wick. In such embodiments a wick may bepositioned to pass through the outer shell during the manufacture of theimplant such that an orifice is not created. In some embodiments, afiber is positioned in an orifice or through the outer shell such aportion of the wick lies adjacent to the drug within the lumen of theimplant. In other embodiments, the drug is formed around the wick, sothat ocular fluid is delivered directly to an interior portion of theagent. In still other embodiments, one or more wicks are used asdescribed above, thus allowing dissolution of the agent from theexterior and interior portions of the pellet or mass of drug.

FIG. 15 shows a cross sectional schematic of one embodiment of animplant in accordance with the description herein and further comprisinga retention protrusion 359 for anchoring the implant to ocular tissue.While depicted in FIG. 15, and other Figures, as having the distalportion being the implant end and the proximal portion being theretention protrusion 359 end, in some embodiments, depending on the siteand orientation of implantation, the distal portion and proximal portionmay be reversed relative to the orientation in FIG. 15. Additionally,while the illustrated implant depicts the presence of orifices that passthrough the outer shell, it shall be appreciated that embodiments of theimplants comprising regions of drug release based on thickness and/orpermeability of the shell material can also be used in conjunction witha retention feature. Moreover, implants comprising combinations of oneor more orifices, one or more layers of permeable and/or semi-permeablematerial, and one or more areas of drug release based on thicknessand/or permeability of the shell material are used in severalembodiments.

In several embodiments, implants comprise a sheet 400 and a retentionprotrusion 359. See FIG. 16. In some embodiments, the sheet is notjoined to a retention protrusion. The sheet can be made of anybiocompatible material, including but not limited to, polymers, fibers,or composite materials. In some embodiments, the sheet is compoundedwith one or more therapeutic agent(s). In some embodiments, the sheet iscoated with a material that is compounded with one or more therapeuticagents. In other embodiments, a sheet compounded with a firsttherapeutic agent is coated with a material compounded with a secondtherapeutic agent, a different concentration of the first therapeuticagent, or an auxiliary agent. In some embodiments the sheet isbiodegradable, while in others it is not. In other embodiments, a disc402 (FIG. 17) is used in place of a sheet. In several embodiments, thesheet or disc is flexible.

For delivery of some embodiments of the sheet or disc implants, thesheets or discs are dimensioned such that they can be rolled, folded, orotherwise packaged within a delivery instrument. In some embodiments,the entire implant is flexible. In some embodiments, the implant ispre-curved or pre-bent, yet still flexible enough to be placed within anon-curved lumen of a delivery apparatus. In some embodiments theflexible sheets or discs have thicknesses ranging from about 0.01 mm toabout 1.0 mm. Preferably, the delivery instrument has a sufficientlysmall cross section such that the insertion site self seals withoutsuturing upon withdrawal of the instrument from the eye, for example anouter dimension preferably no greater than about 18 gauge and is notsmaller than about 27 or 30 gauge. In such embodiments, the rolled orfolded sheets or discs can return to substantially their originaldimensions after attachment to the ocular tissue and withdrawal of thedelivery instrument. In certain embodiments, thicknesses of about 25 to250 microns, including about 50 to 200 microns, about 100 to 150microns, about 25 to 100 microns, and about 100 to 250 microns are used.

The implant is dimensioned, in some embodiments, to be affixed (e.g.,tethered) to the iris and float within the aqueous of the anteriorchamber. In this context, the term “float” is not meant to refer tobuoyancy of the implant, but rather that the sheet surface of theimplant is movable within ocular fluid of the anterior chamber to theextent allowed by the retention protrusion. In certain embodiments, suchimplants are not tethered to an intraocular tissue and are free floatingwithin the eye. In certain embodiments, the implant can be adhesivelyfixed to the iris with a biocompatible adhesive. In some embodiments, abiocompatible adhesive may be pre-activated, while in others, contactwith ocular fluid may activate the adhesive. Still other embodiments mayinvolve activation of the adhesive by an external stimulus, afterplacement of the implant, but prior to withdrawal of the deliveryapparatus. Examples of external stimuli include, but are not limited toheat, ultrasound, and radio frequency, or laser energy. In certainembodiments, affixation of the implant to the iris is preferable due tothe large surface area of the iris. In other embodiments, the implant isflexible with respect to a retention protrusion affixed to the iris, butis not free floating. Embodiments as disclosed herein are affixed to theiris in a manner that allows normal light passage through the pupil.

As discussed above, several embodiments disclosed herein employ multiplematerials of varying permeability to control the rate of drug releasefrom an implant. FIGS. 18A-18Q depict additional implant embodimentsemploying materials with varied permeability to control the rate of drugrelease from the implant. FIG. 18A shows a top view of the implant body53 depicted in FIG. 18B. The implant body 53 comprises the outer shell54 and retention protrusion 359. While not explicitly illustrated, itshall be appreciated that in several embodiments, implants comprising abody and a cap are also constructed without a retentions protrusion.FIG. 18C depicts an implant cap 53 a, which, in some embodiments, ismade of the same material as the outer shell 54. In other embodiments,the cap 53 is made of a different material from the outer shell. Aregion of drug release 56 is formed in the cap through the use of amaterial with permeability different from that of the shell 54. It shallalso be appreciated that implants comprising a body and a cap (andoptionally a retention protrusion) may be constructed with orificesthrough the body or the cap, may be constructed with layers or coatingsof permeable or semi-permeable material covering all or a portion of anyorifices, and may also be constructed with combinations of the above andregions of drug release based on thickness and/or permeability of theshell material. See 18E-18F.

FIGS. 18G-18J depict assembled implants according to several embodimentsdisclosed herein. The implant body 53 is joined with the implant cap 53a, thereby creating a lumen 58 which is filled with a drug 62. In someembodiments, the material of the implant body 54 differs from that ofthe cap 54 a. Thus, the assembly of a cap and body of differingmaterials creates a region of drug release 56.

Additional non-limiting embodiments of caps are shown in FIGS. 18K and18L. In FIG. 18K, an O-ring cap 53 a with a region of drug release 56 isshown in cross-section. In other embodiments there may be one or moreregions of drug release in the cap. An o-ring 99 (or other sealingmechanism) is placed around the cap such that a fluid impermeable sealis made between the cap and the body of the implant when assembled. InFIG. 18L, a crimp cap is shown. The outer shell of the cap comprisesregions that are compressible 98 such that the cap is securely placedon, and sealed to, the body of the implant. As discussed above, certainembodiments employ orifices and layers in place of, or in addition toregions of drug release based on thickness and/or permeability of theshell material. FIG. 18M depicts an O-ring cap 53 a shown incross-section. A coating 60 is placed within the outer shell 54 of thecap and covering an orifice 56 a. In other embodiments there may be oneor more orifices in the cap. In some embodiments, the coating 60comprises a membrane or layer of semi-permeable polymer. In someembodiments, the coating 60 has a defined thickness, and thus a definedand known permeability to various drugs and ocular fluid. In FIG. 18N, acrimp cap comprising an orifice and a coating is shown. While thecoatings are shown positioned within the caps, it shall be appreciatedthat other locations are used in some embodiments, including on theexterior of the cap, within the orifice, or combinations thereof (SeeFIG. 18O).

Additionally, as shown in FIGS. 18P and 18Q, in certain embodiments,coatings are employed within the drug material such that layers areformed. Coatings can separate different drugs 62 a, 62 b, 62 c, 62 dwithin the lumen (FIG. 18P). In certain embodiments, coatings are usedto separate different concentration of the same drug (FIG. 18Q). Itshall be appreciated that such internal layers are also useful inembodiments comprising regions of drug release (either alone or incombination with other drug release elements disclosed herein, e.g.,orifices). In certain embodiments, the layers create a particularlydesired drug elution profile. For example, use of slow-eroding layers isused to create periods of reduced drug release or drug “holidays.”Alternatively, layers may be formulated to create zero order (or otherkinetic profiles) as discussed in more detail below.

In each of the embodiments depicted in the Figures, as well as otherembodiments, the coatings or outer layers of shell material may beformed by spraying, dipping, or added by some other equivalent meansknown in the art. Thus, in some embodiments, the permeability of theregion of drug release or layer(s) covering an orifice (and hence theelution rate) will be at least partially defined by the materials usedin manufacturing the implant, the coatings (if any) on the implant, andthe effective thickness of implant outer shell.

During manufacture of the implants of certain embodiments, one or moreinterior lumen 58 is formed within the outer shell of the implant. Insome embodiments, an interior lumen is localized within the proximalportion of the implant, while in other embodiments, an interior lumenruns the entire length or any intermediate length of the implant. Someembodiments consist of a single interior lumen, while others comprisetwo or more interior lumens. In some embodiments, one or more of theinternal lumens may communicate with an ocular chamber or region, e.g.,the anterior chamber. In some embodiments, implants are dimensioned tocommunicate with more than one ocular chamber or region. In someembodiments, both the proximal and the distal end of the implant arepositioned within a single ocular chamber or region, while in otherembodiments, the ends of the implant are positioned in different ocularchambers or regions.

A drug 62 is housed within the interior lumen 58 of the implant. Thedrug 62 comprises a therapeutically effective agent against a particularocular pathology as well as any additional compounds needed to preparethe drug in a form with which the drug is compatible. In someembodiments, one or more of the internal lumens may contain a differentdrug or concentration of drug, which may be delivered simultaneously(combination therapy) or separately. In some preferred embodiments, aninterior lumen is sized in proportion to a desired amount of drug to bepositioned within the implant. The ultimate dimensions of an interiorlumen of a given embodiment are dictated by the type, amount, anddesired release profile of the drug or drugs to be delivered and thecomposition of the drug(s).

In some embodiments, the drug is in the form of a drug-containingpellet, while in other embodiments, the drug is a liquid, a slurry,micro-pellets (e.g., micro-tablets) or powder. In certain suchembodiments, the form of the drug allows the implant to be flexible. Insome embodiments the drug is compounded with a polymer formulation. Insome embodiments, the drug positioned in the lumen is pure drug. Incertain embodiments, the polymer formulation comprises a poly(lactic-co-glycolic acid) or PLGA co-polymer or other biodegradable orbioerodible polymer. In still other embodiments, the interior lumencontains only drug.

In some embodiments, multiple pellets 62 of single or multiple drug(s)are placed within an interior lumen of the implant. In some embodimentsan impermeable partition 64 is used to seal drug(s) within the lumen,such that the sole route of exit from the implant is through the regionof drug release. In some embodiments, the impermeable partition 64 maybioerode at a specified rate. In some embodiments, the impermeablepartition 64 is incorporated into the drug pellet and creates a sealagainst the inner dimension of the shell of the implant 54. In otherembodiments, more than one impermeable partition is used within a lumen,thereby creating sub-lumens, which may contain different drugs, the samedrug at a different concentration, or the same or another drugcompounded with different excipients etc. In such embodiments,sequential drug release or release of two agents that are inert withinthe implant and active when co-mingled outside their respectivesub-lumens may be achieved.

In some embodiments, the therapeutic agent is formulated asmicro-pellets or micro-tablets. Additionally, in some embodiments,micro-tablets allow a greater amount of the therapeutic agent to be usedin an implant. This is because, in some embodiments, tabletting achievesa greater density in a pellet than can be achieved by packing a device.Greater amounts of drug in a given volume may also be achieved bydecreasing the amount of excipient used as a percentage by weight of thewhole tablet, which has been found by the inventors to be possible whencreating tablets of a very small size while retaining the integrity ofthe tablet. In some embodiments, the percentage of active therapeutic(by weight) is about 70% or higher. As discussed herein, the therapeuticagent can be combined with excipients or binders that are known in theart. In some embodiments, the percentage of therapeutic agent rangesfrom about 70% to about 95%, from about 75 to 85%, from about 75 to 90%,from about 70 to 75%, from about 75% to about 80% from about 80% toabout 85%, from about 85% to about 90%, from about 90% to about 95%,from about 95% to about 99%, from about 99% to about 99.9%, andoverlapping ranges thereof. In some embodiments, the percentage oftherapeutic agent ranges from about 80% to about 85%, including 81, 82,83, and 84% by weight.

In several embodiments, micro-tablets provide an advantage with respectto the amount of an agent that can be packed, tamped, or otherwiseplaced into an implant disclosed herein. The resultant implantcomprising micro-tablets, in some embodiments, thus comprisestherapeutic agent at a higher density than can be achieved withnon-micro-tablet forms. For example, in some embodiments, the density ofthe micro-pellet form of an agent within an implant ranges from about0.7 g/cc to about 1.6 g/cc. In some embodiments, the density used in animplant ranges from about 0.7 g/cc to about 0.9 g/cc, from about 0.9g/cc to about 1.1 g/cc, from about 1.1 g/cc to about 1.3 g/cc, fromabout 1.1 g/cc to about 1.5 g./cc, from about 1.3 g/cc to about 1.5g/cc, from about 1.5 g/cc to about 1.6 g/cc, and overlapping rangesthereof. In some embodiments, densities of therapeutic agent that aregreater than 1.6 g/cc are used.

As described herein, some embodiments of the devices disclosed hereinare rechargeable, and as such, the size of micro-tablets isadvantageous. In some embodiments, the loading and/or recharging of adevice is accomplished with a syringe/needle, through which thetherapeutic agent is delivered. In some embodiments, micro-tablets aredelivered through a needle of about 23 gauge to about 32 gauge,including 23-25 gauge, 25 to 27 gauge, 27-29 gauge, 29-30 gauge, 30-32gauge, and overlapping ranges thereof. In some embodiments, the needleis 23, 25, 27, 30, or 32 gauge. In some embodiments, the micro-tabletsmay be introduced into the eye directly, such as into the vitreouscavity, using a syringe or cannula.

In one embodiment, micro-tablets with the above properties, or anycombination thereof, are made using known techniques in the artincluding tableting, lyophilization, granulation (wet or dry), flaking,direct compression, molding, extrusion, and the like. Moreover, asdiscussed below, alterations in the above discussed characteristics canbe used to tailor the release profile of the micro-tableted therapeuticagent from an implant.

In several embodiments, lyophilization of a therapeutic agent is usedprior to the micro-pelleting process. In some embodiments,lyophilization improves the stability of the therapeutic agent onceincorporated into a micro-tablet. In some embodiments, lyophilizationallows for a greater concentration of therapeutic to be obtained priorto micro-pelleting, thereby enhancing the ability to achieve the highpercentages of active therapeutic agents that are desirable in someembodiments. For example, many commercially available therapeutic agentsuseful to treat ocular diseases are developed as first-line agents forother diseases. As such, their original formulation may not be suitableor ideal for micro-pelleting or for administration to an ocular targetvia an ocular implant such as those disclosed herein. For example,several anti-VEGF compounds are supplied as sterile liquid in single usevials meant to be administered intravenously (e.g., bevacizumab). As aresult, such a liquid formulation is less preferred for formation ofmicro-pellets as compared to a solid, though a liquid therapeutic agentmay optionally be used in some embodiments. To achieve micro-pelletingat high percentages of therapeutic agent, such liquid formulations maybe frozen (e.g., stored at temperatures between −20 and −80 C for 16 to24 hours or longer) and then subject to lyophilization until dry.Alternatively, air spraying, crystallization, or other means mayoptionally be used to dry the therapeutic agent.

Once dry, the lyophilized (or otherwise dried) therapeutic agent isoptionally tested for purity. In some embodiments, solvents may be addedto a liquid (or solid) formulation in order to dissolve and remove (viaevaporation) non-therapeutic components (e.g., excipients or inertbinding agents). In some embodiments, a therapeutic agent is purified byconventional methods (e.g., antibody-based chromatography, HPLC, etc.)prior to lyophilization. In such embodiments, lyophilization oftenfunctions to increase the concentration of the therapeutic agent in therecovered purified sample.

In some embodiments, the dried therapeutic agent (which, for efficiencypurposes is optionally dried in bulk) is ground, sieved, macerated,freeze-fractured, or subdivided into known quantities by other means,and then micro-pelleted.

After lyophilization and or subdivision, the therapeutic agent is fedinto a micro-pelleting process. In some embodiments, standard techniques(e.g., compression, extrusion, molding, or other means) are used.However, in several embodiments employing high percentages of activetherapeutic agent, more specialized techniques are used.

In several embodiments, the therapeutic agent is a protein, and in suchembodiments, drying and/or tabletization should be completed underconditions (e.g., temperature, acid/base, etc.) that do not adverselyaffect the biological activity of the therapeutic agent. To assist inmaintenance of biological activity of micro-pelleted therapeutic agents,in some embodiments, protein therapeutics are formulated with astabilizing agent (e.g., mannitol, trehalose, starch, or otherpoly-hydroxy polymer) to maintain the structure (and therefore activity)of the therapeutic protein.

FIGS. 19A-19W illustrate embodiments of drug various embodiments ofretention protrusions. As used herein, retention protrusion is to begiven its ordinary meaning and may also refer to any mechanism or anchorelement that allows an implant to become affixed, anchored, or otherwiseattached, either permanently or transiently, to a suitable targetintraocular tissue (represented generally as 15 in FIGS. 19A-19G). Forexample, a portion of an implant that comprises a biocompatible adhesivemay be considered a retention protrusion, as may barbs, barbs withholes, screw-like elements, knurled elements, and the like. In someembodiments, implants are sutured to a target tissue. For example, insome embodiments, implants are sutured to the iris, preferably theinferior portion. It should be understood that any retention means maybe used with any illustrated (and/or described) implant (even if notexplicitly illustrated or described as such). In some embodiments,implants as described herein are wedged or trapped (permanently ortransiently) based on their shape and/or size in a particular desirableocular space. For example, in some embodiments, an implant (e.g., asuprachoroidal stent) is wedged within an ocular space (e.g., thesuprachoroidal space) based on the outer dimensions of the implantproviding a sufficient amount of friction against the ocular tissue tohold the implant in place.

Intraocular targets for anchoring of implants include, but are notlimited to the fibrous tissues of the eye. In some embodiments, implantsare anchored to the ciliary muscles and/or tendons (or the fibrousband). In some embodiments, implants are anchored into Schlemm's canal,the trabecular meshwork, the episcleral veins, the iris, the iris root,the lens cortex, the lens epithelium, the lens capsule, the sclera, thescleral spur, the choroid, the suprachoroidal space, the anteriorchamber wall, or disposed within the anterior chamber angle. As usedherein, the term “suprachoroidal space” shall be given its ordinarymeaning and it will be appreciated that other potential ocular spacesexist in various regions of the eye that may be encompassed by the term“suprachoroidal space.” For example, the suprachoroidal space located inthe anterior region of the eye is also known as the supraciliary space,and thus, in certain contexts herein, use of “suprachoroidal space”shall be meant to encompass the supraciliary space.

The retention protrusions may be formulated of the same biocompatiblematerial as the outer shell. In some embodiments the biodegradableretention protrusions are used. In alternate embodiments, one or more ofthe retention protrusions may be formed of a different material than theouter shell. Different types of retention protrusions may also beincluded in a single device.

In some embodiments, see for example FIG. 19A, the retention protrusion359 may comprise a ridged pin 126 comprising a ridge 128 or series ofridges formed on the surface of a base portion 130. Such ridges may beformed in any direction on the surface of the implant including, but notlimited to, biased from the long axis of the implant, spiraling aroundthe implant, or encircling the implant (see, e.g. FIG. 19B). Likewise,the ridges may be distinct or contiguous with one another. Otheranchoring elements may also be used, such as raised bumps; cylinders;deep threads 134, as shown in FIG. 19C; ribs 140, as shown in FIG. 19D;a rivet shaped base portion 146, as shown in FIG. 19E; biocompatibleadhesive 150 encircling the retention element 359 where it passesthrough an ocular tissue, as shown in FIG. 19F; or barbs 170, as shownin FIG. 19G. In some embodiments, the retention protrusion is positionedwithin a pre-existing intraocular cavity or space, shown generally as20. For example, as depicted in FIG. 19H, an elongated blade 34 resideswithin Schlemm's canal 22 and is attached to a base portion 130 thattraverses the trabecular meshwork 21. In other embodiments, as depictedin FIG. 19I, based on the dimensions of intraocular spaces, which arewell-known in the art, a shorter base 130 a is used and attached to theelongated blade 34 residing within Schlemm's canal 22.

In certain embodiments, an expandable material 100 is used inconjunction with or in place of a physical retention protrusion. Forexample, in FIG. 19J, the base 130 is covered, in particular areas, withan expandable material 100. Upon contact with an appropriate solvent,which includes ocular fluid, the material expands (as depicted by thearrows), thus exerting pressure on the surrounding tissue, for examplethe trabecular meshwork 21 and base of Schlemm's canal 22 in FIG. 19J.

In some embodiments, an external stimulus is used to induce theexpansion of the expandable material 100. As depicted in FIG. 19K, thebase 130 is covered, in particular areas, with an expandable material100. Upon stimulation by an external stimuli hv, the material expands(as depicted by the arrows), thus exerting pressure on the surroundingtissue, for example the trabecular meshwork 21 and base of Schlemm'scanal 22 in FIG. 19K. Suitable external stimuli include, but are notlimited to, light energy, electromagnetic energy, heat, ultrasound,radio frequency, or laser energy.

In several other embodiments, the expandable material 100, is coated orlayered on the outer shell 54, which expands in response to contact witha solvent. See FIGS. 19L-19Q. In some embodiments, once the implant isfully positioned within the desired intraocular space, contact withbodily fluid causes the expandable material to swell, solidify or gel,or otherwise expand. (Compare dimension D to D₁ in FIGS. 19L-19Q). As aresult, the expanded material exerts pressure on the surrounding oculartissue, which secures in the implant in position.

In some embodiments, the expanding material fills any voids between theimplant shell and the surrounding intraocular tissue. In some suchembodiments, the expanded material seals one portion of the implant offfills or otherwise seals the volume around the implant outer shell suchthat fluid is prevented from flowing around the implant, and must flowthrough the implant.

In other embodiments, such as those schematically depicted in FIGS. 19Pand 19Q, the expandable material 100 is positioned on selected areas ofthe implant shell 54, such that the expanded material exerts pressure onthe surrounding ocular tissue, but also maintains the patency of anatural ocular fluid passageway by the creation of zones of fluid flow102 around the implant shell and expandable material. In still otherembodiments, the expandable material can be positioned within the lumenof the implant, such that the expansion of the material assists orcauses the lumen to be maintained in a patent state.

The expandable material can be positioned on the implant by dipping,molding, coating, spraying, or other suitable process known in the art.

In some embodiments, the expandable material is a hydrogel or similarmaterial. Hydrogel is a three-dimensional network of cross-linked,hydrophilic polymer chains. The hydrophilicity of the polymer chainscause the hydrogel to swell in the presence of sufficient quantities offluid. In other embodiments, the expandable material is foam, collagen,or any other similar biocompatible material that swells, solidifies orgels, or otherwise expands. In some embodiments, the expandable materialbegins to expand immediately on contact with an appropriate solvent. Inother embodiments, expansion occurs after passage of a short period oftime, such that the implant can be fully positioned in the desiredtarget site prior to expansion of the material. Preferred solvents thatinduce expansion include water, saline, ocular fluid, aqueous humor, oranother biocompatible solvents that would not affect the structure orpermeability characteristics of the outer shell.

The expansion of the expandable material is varied in severalembodiments. In some embodiments, as described above, the material ispositioned on the outer shell of implant such that the expanded materialexerts pressure on the surrounding ocular tissue, thereby securing theimplant in position. In other embodiments, the expandable material maybe placed adjacent to, surrounding, or under another anchoring element(such as those described above), such that the expansion of theexpandable material causes the anchoring element to move from a first,retracted state to a second, expanded state wherein the anchoringelement anchors the implant against an ocular structure in the expandedstate. In some embodiments, the expandable material is designed toexpand only in two dimensions, while in other embodiments, the materialexpands in three dimensions.

Although FIGS. 19L and 19M depict the expandable material as rectangularin cross-section, it will be appreciated that the cross-sectional shapecan vary and may include circular, oval, irregular, and other shapes incertain embodiments. The relative expansion (change from dimension D toD₁) of the material is also controlled in several embodiments. Incertain embodiments the D to D₁ change is greater than in otherembodiments, while in some embodiments, a smaller D to D₁ change isrealized upon expansion of the material.

FIGS. 19P and 19Q show side views of an implant having expandableanchoring elements 100 comprising projections extending radially outwardfrom the body of the implant. In some such embodiments, the anchoringelements are individually connected to the implant body, while in otherembodiments, they are interconnected by a sheath region that mounts overthe implant body.

In selected embodiments, the implant and/or the retention protrusionadditionally includes a shunt feature. The term “shunt” as used hereinis abroad term, and is to be given its ordinary and customary meaning toa person of ordinary skill in the art (and it is not to be limited to aspecial or customized meaning), and refers without limitation to theportion of the implant defining one or more fluid passages for transportof fluid from a first, often undesired location, to one or more otherlocations. The term “stent” may also be used to refer to a shunt. Insome embodiments, the shunt can be configured to provide a fluid flowpath for draining aqueous humor from the anterior chamber of an eye toan outflow pathway to reduce intraocular pressure, for example, as inFIGS. 19R-19T. In still other embodiments, the shunt feature of theimplant may be positioned in any physiological location thatnecessitates simultaneous drug delivery and transport of fluid from afirst physiologic site to a second site (which may be physiologic orexternal to a patient).

The shunt portion of the implant can have an inflow portion 38 k and oneor more outflow portions 56 k. In some embodiments, the inflow andoutflow portions are positioned at various locations on the implantdepending on the physiological space in which they are to be located. Asshown in FIG. 19R, the outflow portion may be disposed at or near theproximal end 52 of the implant. When the implant is deployed, the inflowportion may be sized and configured to reside in the anterior chamber ofthe eye and the outflow portion may be sized and configured to residewithin the trabecular meshwork 23 or Schlemm's canal 22. In otherembodiments, the outflow portion may be sized and configured to residein the supraciliary region of the uveoscleral outflow pathway, thesuprachoroidal space, other part of the eye, or within otherphysiological spaces amenable to fluid deposition.

At least one lumen can extend through the shunt portion of the implant.In some embodiments, there is at least one lumen that operates toconduct the fluid through the shunt portion of the implant. In certainembodiments, each lumen extends from an inflow end to an outflow endalong a lumen axis. In some embodiments the lumen extends substantiallythrough the longitudinal center of the shunt. In other embodiments, thelumen can be offset from the longitudinal center of the shunt.

As discussed above, in some embodiments, a compressed pellet of drug notcoated by an outer shell 62 is attached or otherwise coupled to animplant comprising a shunt and a retention feature. As depicted in FIG.19T, the shunt portion of the implant comprises one or more inflowportions 38 k and one or more outflow portions 56 k. In someembodiments, the inflow portions are positioned in a physiological spacethat is distinct from the outflow portions. In some embodiments, such apositioning allows for fluid transport from a first location to a secondlocation. For example, in some embodiments, when deployed intraocularly,the inflow portions are located in the anterior chamber and the outflowportions are located in Schlemm's canal 22. In this manner, ocular fluidthat accumulates in the anterior chamber is drained from the anteriorchamber into Schlemm's canal, thereby reducing fluid pressure in theanterior chamber. In other embodiments, the outflow portion may be sizedand configured to reside in the supraciliary region of the uveoscleraloutflow pathway, the suprachoroidal space, other part of the eye, orwithin other physiological spaces amenable to fluid deposition.

Additional embodiments comprising a shunt may be used to drain ocularfluid from a first location to different location. As depicted in FIG.19U, a shunt 30 p directs aqueous from the anterior chamber 20 directlyinto a collector channel 29 which empties into aqueous veins. The shunt30 p has a distal end 160 that rests against the back wall of Schlemm'scanal. A removable alignment pin 158 is utilized to align the shuntlumen 42 p with the collector channel 29. In use, the pin 158 extendsthrough the implant lumen and the shunt lumen 42 p and protrudes throughthe base 160 and extends into the collector channel 29 to center and/oralign the shunt 30 p over the collector channel 29. The shunt 30 p isthen pressed firmly against the back wall 92 of Schlemm's canal 22. Apermanent bio-glue 162 is used between the shunt base and the back wall92 of Schlemm's canal 22 to seat and securely hold the shunt 30 p inplace. Once positioned, the pin 158 is withdrawn from the shunt andimplant lumens 42 p to allow the aqueous to flow from the anteriorchamber 20 through the implant, through the shunt, and into thecollector duct 29. The collector ducts are nominally 20 to 100micrometers in diameter and are visualized with a suitable microscopymethod (such as ultrasound biomicroscopy (UBM)) or laser imaging toprovide guidance for placement of the shunt 30 p. In another embodiment,the pin 158 is biodegradable in ocular fluid, such that it need not bemanually removed from the implant.

In some embodiments, the shunt 30 p is inserted through a previouslymade incision in the trabecular meshwork 23. In other embodiments, theshunt 30 p may be formed with blade configuration to provideself-trephining capability. In these cases, the incision through thetrabecular meshwork 23 is made by the self-trephining shunt device whichhas a blade at its base or proximate to the base.

As shown in FIG. 19V, a shunt extending between an anterior chamber 20of an eye, through the trabecular meshwork 23, and into Schlemm's canal22 of an eye can be configured to be axisymmetric with respect to theflow of aqueous therethrough. For example, as shown in FIG. 19V, theshunt 229A comprises an inlet end 230 configured to be disposed in theanterior chamber 20 and associated with a drug delivery implant inaccordance with embodiments disclosed herein. For clarity of the shuntfeature, the implant is not shown. The second end 231 of the shunt 229Ais configured to be disposed in Schlemm's canal 22. At least one lumen239 extends through the shunt 229A between the inlet and outlet ends230, 232. The lumen 239 defines an opening 232 at the inlet end 230 aswell as an outlet 233 at the outlet end 231.

In the illustrated embodiment, an exterior surface 238 of the shunt 229Ais cone-shaped. Thus, a circumference of the exterior surface 238adjacent to the inlet end 230 is smaller than the circumference of theouter surface 238 at the outlet end 231.

With the shunt 229A extending through the trabecular meshwork 23, thetissue of the trabecular meshwork 23 provides additional anchoring forcefor retaining the shunt 229A with its inlet end 230 in the anteriorchamber and its outlet end 231 in Schlemm's canal. For example, thetrabecular meshwork 23 would naturally tend to close an apertureoccupied by the shunt 229A. As such, the trabecular meshwork 23 wouldtend to squeeze the shunt 229A. Because the exterior surface 238 isconical, the squeezing force applied by the trabecular meshwork 23 wouldtend to draw the shunt 229A towards Schlemm's canal 22. In theillustrated embodiment, the shunt 229A is sized such that a portion 234of the shunt 229 adjacent to the inlet end 230 remains in the anteriorchamber 20 while a portion 235 of the shunt 229 adjacent to the outletend 231 remains in Schlemm's canal 22.

In the illustrated embodiment, the outer surface 238 of the shunt 229Ais smooth. Alternatively, the outer surface 238 can have other contourssuch as, for example, but without limitation curved or stepped. In oneembodiment, the outer surface 238 can be curved in a concave manner soas to produce a trumpet-like shape. Alternatively, the outer surface 238can be convex.

In certain embodiments, the shunt 229A preferably includes one orplurality of posts or legs 236 configured to maintain a space betweenthe outlet opening 233 and a wall of Schlemm's canal 22. As such, thelegs 236 prevent a wall of Schlemm's canal from completely closing offthe outlet opening 233 of the shunt 229A. In the illustrated embodiment,the legs 236 are coupled to the distal-most surface of the shunt 229Aand are substantially parallel to an implant axis extending through theshunt 229A and between the anterior chamber 20 and Schlemm's canal 22.

This arrangement of the legs 236 and the outlet 233 imparts anaxisymmetric flow characteristic to the shunt 229A. For example, aqueouscan flow from the outlet 233 in any direction. Thus, the shunt 229A canbe implanted into Schlemm's canal at any angular position relative toits implant axis. Thus, it is not necessary to determine the angularorientation of the shunt 229A prior to implantation, nor is it necessaryto preserve a particular orientation during an implantation procedure.

FIG. 19W illustrates a modification of the shunt 229A, identifiedgenerally by the reference numeral 229B. In this embodiment, the shunt229B includes a flange 237 extending radially from the portion 234.Preferably, the flange 237 is configured to retain the first portion 234within the anterior chamber 20. It is to be recognized that althoughgenerally, aqueous will flow from the anterior chamber 20 towardsSchlemm's canal 22, the shunt 229A, 229B or any of the above-describedshunts as well as other shunts described below, can provide foromni-directional flow of aqueous.

FIG. 19X illustrates another modification of the shunt 229A, identifiedgenerally by the reference numeral 229C. In this embodiment, the outersurface 238C is not conical. Rather, the outer surface 238C iscylindrical. The shunt 229C includes a flange 240 that can be the samesize and shape as the flange 237. The legs 236C extend from the flange240.

Constructed as such, the natural tendency of the tissue of thetrabecular meshwork 21 to close the hole in which the shunt 229C isdisposed, aids in anchoring the shunt 229C in place. Additionally, thelegs 236C aid in preventing the walls of Schlemm's canal from completelyclosing the outlet 233C of the lumen 239C.

With reference to FIG. 19Y, another embodiment of an axisymmetrictrabecular shunting device is illustrated therein and identifiedgenerally by the reference numeral 229F.

The shunt 229F comprises an inlet (proximal) section having a firstflange 240F, an outlet (distal) section having a second flange 237F anda middle section 284 connecting the inlet section and the outletsection. A lumen 239F of the device 229F is configured to transportaqueous, liquid, or therapeutic agents between the inlet section and theoutlet section.

The inlet section of the shunt 229F has at least one inlet opening 286and the outlet section comprises at least one outlet opening 287. Insome embodiments, the inlet opening 286 is directly associated with theproximal end of an implant, such that ocular fluid flowing through alumen of the implant passes into the lumen 239F of the shunt. In otherembodiments, the shunt is joined or associated with an implant in amanner where the inlet opening 286 receives ocular fluid directly froman ocular cavity, without having first passed through the implant. Instill other embodiments, the shunt carries fluid from both sources(e.g., from the eye and from the implant lumen).

A further advantage of such embodiments is provided where the outletsection 237F includes at least one opening 287, 288 suitably located fordischarging substantially axisymmetrically the aqueous, liquid ortherapeutic agents, wherein the opening 287, 288 is in fluidcommunication with the lumen 285 of the device 281. In the illustratedembodiment, the openings 288 extend radially from the lumen 285 and openat the outwardly facing surface around the periphery of the outletflange 237F.

It should be understood that all such anchoring elements and retentionprotrusions may also be made flexible. It should also be understood thatother suitable shapes can be used and that this list is not limiting. Itshould further be understood the devices may be flexible, even thoughseveral of the devices as illustrated in the Figures may not appear tobe flexible. In those embodiments involving a rechargeable device, theretention protrusions not only serve to anchor the implant, but provideresistance to movement to allow the implant to have greater positionalstability within the eye during recharging.

For the sake of clarity, only a small number of the possible embodimentsof the implant have been shown with the various retention projections.It should be understood that any implant embodiment may be readilycombined with any of the retention projections disclosed herein, andvice versa.

It will further be appreciated that, while several embodiments describedabove are shown, in some cases as being anchored within or to particularintraocular tissues, that each embodiment may be readily adapted to beanchored or deployed into or onto any of the target intraocular tissuesdisclosed herein or to other ocular tissues known in the art.

Additionally, while embodiments described both above and below includediscussion of retention projections, it will be appreciated that severalembodiments of the implants disclosed herein need not include a specificretention projection. Such embodiments are used to deliver drug toocular targets which do not require a specific anchor point, andimplants may simply be deployed to a desired intraocular space. Suchtargets include the vitreous humor, the ciliary muscle, ciliary tendons,the ciliary fibrous band, Schlemm's canal, the trabecular meshwork, theepiscleral veins, the anterior chamber and the anterior chamber angle,the lens cortex, lens epithelium, and lens capsule, the ciliaryprocesses, the posterior chamber, the choroid, and the suprachoroidalspace. For example, in some embodiments, an implant according to severalembodiments described herein is injected (via needle or otherpenetrating delivery device) through the sclera at a particularanatomical site (e.g., the pars plana) into the vitreous humor. Suchembodiments need not be constructed with a retention protrusion, thus itwill be appreciated that in certain embodiments, the use of a retentionprotrusion is optional for a particular target tissue.

Some embodiments disclosed herein are dimensioned to be wholly containedwithin the eye of the subject, the dimensions of which can be obtainedon a subject to subject basis by standard ophthalmologic techniques.Upon completion of the implantation procedure, in several embodiments,the proximal end of the device may be positioned in or near the anteriorchamber of the eye. The distal end of the implant may be positionedanywhere within the suprachoroidal space. In some embodiments, thedistal end of the implant is near the limbus. In other embodiments, thedistal end of the implant is positioned near the macula in the posteriorregion of the eye. In other embodiments, the proximal end of the devicemay be positioned in or near other regions of the eye. In some suchembodiments, the distal end of the device may also be positioned in ornear other regions of the eye. As used herein, the term “near” is usedat times to as synonymous with “at,” while other uses contextuallyindicate a distance sufficiently adjacent to allow a drug to diffusefrom the implant to the target tissue. In still other embodiments,implants are dimensioned to span a distance between a first non-ocularphysiologic space and a second non-ocular physiologic space.

In one embodiment, the drug delivery implant is positioned in thesuprachoroidal space by advancement through the ciliary attachmenttissue, which lies to the posterior of the scleral spur. The ciliaryattachment tissue is typically fibrous or porous, and relatively easy topierce, cut, or separate from the scleral spur with the deliveryinstruments disclosed herein, or other surgical devices. In suchembodiments, the implant is advanced through this tissue and liesadjacent to or abuts the sclera once the implant extends into theuveoscleral outflow pathway. The implant is advanced within theuveoscleral outflow pathway along the interior wall of the sclera untilthe desired implantation site within the posterior portion of theuveoscleral outflow pathway is reached.

In some embodiments the total length of the implant is between 2 and 30mm in length. In some embodiments, the implant length is between 2 and25 mm, between 6 and 25 mm, between 8 and 25 mm, between 10 and 30 mm,between 15 and 25 mm or between 15 and 18 mm. In some embodiments thelength of the implant is about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, or 25 mm. So that that the delivery devicecontaining an implant can be inserted and advanced through the cornea tothe iris and produce only a self-sealing puncture in the cornea, in someembodiments, the outer diameter of the implants am between about 100 and600 microns. In some embodiments, the implant diameter is between about150-500 microns, between about 125-550 microns, or about 175-475microns. In some embodiments the diameter of the implant is about 100,125, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375,400, 425, 450, 460, 470, 475, 480, 490, or 500 microns. In someembodiments, the inner diameter of the implant is from about between50-500 microns. In some embodiments, the inner diameter is between about100-450 microns, 150-500 microns, or 75-475 microns. In someembodiments, the inner diameter is about 80, 90, 100, 110, 125, 150,175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 410, 420, 425, 430,440, or 450 microns. In some embodiments, including but not limited tothose in which the device is disc or wafer-shaped, the thickness is fromabout 25 to 250 microns, including about 50 to 200 microns, about 100 to150 microns, about 25 to 100 microns, and about 100 to 250 microns.

In further embodiments, any or all of the interior lumens formed duringthe manufacture of the implants may be coated with a layer ofhydrophilic material, thereby increasing the rate of contact of ocularfluid with the therapeutic agent or agents positioned within the lumen.In one embodiment, the hydrophilic material is permeable to ocular fluidand/or the drug. Conversely, any or all of the interior lumens may becoated with a layer of hydrophobic material, to coordinately reduce thecontact of ocular fluid with the therapeutic agent or agents positionedwithin the lumen. In one embodiment, the hydrophobic material ispermeable to ocular fluid and/or the drug.

Selected embodiments of the drug delivery implants described hereinallow for recharging of the implant, i.e. refilling the implant withadditional (same or different) therapeutic agent. In the embodimentsshown in FIGS. 20A-20C, the proximal end 52 of the implant is open andinteracts with a recharging device 80. The recharging device 80comprises a clamping sleeve 72 that houses flexible clamping grippers 74that interacts with the proximal end 52 of the implant. A flexiblepusher tube 76 that may be spring loaded contains a small internalrecess 78 that holds the new therapeutic agent 62 for delivery to theimplant lumen 58. In FIG. 20A, a new dose of agent, coated in a shelland capped with proximal barrier is inserted into the lumen of theimplant. FIGS. 20B and 20C depict recharging the implant with multipledrug pellets. In such embodiments, a one-way passage 70 allows theinsertion of a recharging device carrying a drug pellet into the lumenof the implant, but upon removal of the recharging device, the passagecloses to prevent the drug from escaping the lumen. In addition toproviding the ability to renew dose of drug in the implant, rechargingan implant with multiple pellets may provide one or more other benefits.In some embodiments, the pellets are sized to allow an increased surfacearea of drug that is exposed to ocular fluids (as compared to an implantpacked with a solid drug core). As the exposure to ocular fluid is onevariable in the overall elution rate of a drug, in such embodiments, thesize of the pellets may be adjusted as needed to provide a particulardesired release rate. Moreover, in certain embodiments, the size of themultiple pellets is adjusted to provide a greater rate or capacity forfluid to flow through the lumen of the implant, even when a full drugload is present. Furthermore, one or more of the multiple pellets, incertain embodiments, is coated in order to regulate the dissolution orelution of the drug. It shall be appreciated that, as discussed forcoatings in relation to the implant itself, the pellets may be coatedwith coatings of various thickness, compositions, with or withoutapertures, etc., in order to control the rate of drug release from thepellet itself. In some embodiments, coated pellets are used in anon-coated device, while in other embodiments, combinations of coatedand uncoated pellets are used with coated devices. For example, if anocular condition is known to require drug therapy in addition toremoval/diversion of ocular fluid, the pellets can be sized to deliver asufficient quantity of drug to provide a therapeutic effect andsimultaneously allow ocular fluid to flow through the lumen of theimplant from a first location to a second location. Additionally, thepresence of multiple pellets, or a plurality of particles, as opposed toa single solid core of drug, allows, in certain embodiments, the implantto be flexible. In such embodiments, the shape of the pellets may bedesigned to provide space around the periphery of the pellets such thatthe implant is able to articulate as needed to fit within or adjacent toa desired physiological space without inhibition of this articulationfrom pellet to pellet contact. It shall be appreciated that in suchembodiments, the pellets may contact one another to some degree, stillallowing for a high degree of efficiency in packing the implant withdrug. It shall also be appreciated that in certain embodiments whereflexibility of the implant is unnecessary or undesirable, the pelletsmay be shaped to contact one another more fully, thereby supplementingthe rigidity of an implant.

It will be appreciated that the elements discussed above are not to beread as limiting the implants to the specific combinations orembodiments described. Rather, the features discussed are freelyinterchangeable to allow flexibility in the construction of a drugdelivery implant in accordance with this disclosure.

Delivery Instruments

Another aspect of the systems and methods described herein relates todelivery instruments for implanting an implant for delivering a drug tothe eye and optionally for draining fluid from the anterior chamber intoa physiologic outflow space. In some embodiments, the implant isinserted into the eye from a site transocularly situated from theimplantation site. The delivery instrument is sufficiently long toadvance the implant transocularly from the insertion site across theanterior chamber to the implantation site. At least a portion of theinstrument may be flexible. The instrument may comprise a plurality ofmembers longitudinally moveable relative to each other. In someembodiments, the plurality of members comprises one or more slideableguide tubes. In some embodiments, at least a portion of the deliveryinstrument is curved. In some embodiments, a portion of the deliveryinstrument is rigid and another portion of the instrument is flexible.

In some embodiments, the delivery instrument has a distal curvature. Thedistal curvature of the delivery instrument may be characterized in someembodiments as a radius of approximately 10 to 30 mm. In someembodiments the distal curvature has a radius of about 20 mm.

In some embodiments, the delivery instrument has a distal angle 88 (witha measure denoted by χ in FIG. 21). The angle measure χ may becharacterized as approximately 90 to 180 degrees relative to theproximal segment 94 of the delivery instrument. In some embodiments, theangle measure χ may be characterized as between about 145 and about 170degrees. In some embodiments the angle measure is between about 150 andabout 170 degrees, or between about 155 and about 165 degrees. The anglecan incorporate a small radius of curvature at the “elbow” so as to makea smooth transition from the proximal segment of the delivery instrumentto the distal segment. The length of the distal segment may beapproximately 0.5 to 7 mm in some embodiments, while in some otherembodiments, the length of the distal segment is about 2 to 3 mm.

In other embodiments, a curved distal end is preferred. In suchembodiments, the height of the delivery instrument/shunt assembly(dimension 90 in FIG. 22) is less than about 3 mm in some embodiments,and less than 2 mm in other embodiments.

In some embodiments, the instruments have a sharpened feature at theforward end and are self-trephinating, i.e., self-penetrating, so as topass through tissue without pre-forming an incision, hole or aperture.In some embodiments, instruments that are self-trephinating areconfigured to penetrate the tissues of the cornea and/or limbus only. Inother embodiments, instruments that are self-trephinating are configuredto penetrate internal eye tissues, such as those in the anterior chamberangle, in order to deliver an implant. Alternatively, a separate trocar,scalpel, spatula, or similar instrument can be used to pre-form anincision in the eye tissue (either the cornea/sclera or more internaltissues) before passing the implant into such tissue. In someembodiments, the implant is blunt at the distal end, to aid in bluntdissection (and hence reduce risk of tissue trauma) of the oculartissue. In other embodiments, however, the implant is also sharpened,tapered or otherwise configured to penetrate ocular tissues to aid inimplantation.

For delivery of some embodiments of the drug eluting ocular implant, theinstrument has a sufficiently small cross section such that theinsertion site self seals without suturing upon withdrawal of theinstrument from the eye. An outer dimension of the delivery instrumentis preferably no greater than about 18 gauge and is not smaller thanabout 27 or 30 gauge.

For delivery of some embodiments of the drug eluting ocular implant, anincision in the corneal tissue is made with a hollow needle throughwhich the implant is passed. The needle has a small diameter size (e.g.,18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 gauge) so thatthe incision is self sealing and the implantation occurs in a closedchamber with or without viscoelastic. A self-sealing incision may alsobe formed using a conventional “tunneling” procedure in which aspatula-shaped scalpel is used to create a generally inverted V-shapedincision through the cornea. In a preferred mode, the instrument used toform the incision through the cornea remains in place (that is, extendsthrough the corneal incision) during the procedure and is not removeduntil after implantation. Such incision-forming instrument either may beused to place the ocular implant or may cooperate with a deliveryinstrument to allow implantation through the same incision withoutwithdrawing the incision-forming instrument. Of course, in other modes,various surgical instruments may be passed through one or more cornealincisions multiple times.

Some embodiments include a spring-loaded pusher system. In someembodiments, the spring-loaded pusher includes a button operablyconnected to a hinged rod device. The rod of the hinged rod deviceengages a depression in the surface of the pusher, keeping the spring ofthe pusher in a compressed conformation. When the user pushes thebutton, the rod is disengaged from the depression, thereby allowing thespring to decompress, thereby advancing the pusher forward.

In some embodiments, an over-the wire system is used to deliver theimplant. The implant may be delivered over a wire. In some embodiments,the wire is self-trephinating. The wire may also function as a trocar.The wire may be superelastic, flexible, or relatively inflexible withrespect to the implant. The wire may be pre-formed to have a certainshape. The wire may be curved. The wire may have shape memory, or beelastic. In some embodiments, the wire is a pull wire. The wire may alsobe a steerable catheter.

In some embodiments, the wire is positioned within a lumen in theimplant. The wire may be axially movable within the lumen. The lumen mayor may not include valves or other flow regulatory devices.

In some embodiments, the delivery instrument is a trocar. The trocar maybe angled or curved. In some embodiments, the trocar is flexible. Inother embodiments the trocar is relatively rigid. In other embodiments,the trocar is stiff. In embodiments where the trocar is stiff, theimplant is relatively flexible. The diameter of the trocar is about0.001 inches to about 0.01 inches. In some embodiments, the diameter ofthe trocar is 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008,0.009, or 0.01 inches.

In some embodiments, delivery of the implant is achieved by applying adriving force at or near the proximal end of the implant. The drivingforce may be a pulling or a pushing applied to the end of the implant.

The instrument may include a seal or coating to prevent aqueous humorfrom passing through the delivery instrument and/or between the membersof the instrument when the instrument is in the eye. The seal aids inpreventing backflow. In some embodiments, the instrument is coated withthe coating and a hydrophilic or hydrophobic agent. In some embodiments,one region of the instrument is coated with the coating plus thehydrophilic agent, and another region of the instrument is coated withthe coating plus the hydrophobic agent. The delivery instrument mayadditionally comprise a seal between various members comprising theinstrument. The seal may comprise a hydrophobic or hydrophilic coatingbetween slip-fit surfaces of the members of the instrument. The seal maybe disposed proximate of the implant when carried by the deliveryinstrument. In some embodiments, the seal is present on at least asection of each of two devices that are machined to closely fit with oneanother.

The delivery instrument may include a distal end having a beveled shape.The delivery instrument may include a distal end having a spatula shape.The beveled or spatula shape may or may not include a recess to containthe implant. The recess can include a pusher or other suitable means topush out or eject the implant.

The delivery instrument may be configured to deliver multiple implants.In some such embodiments, the implants may be arranged in tandem (orserially for implant numbers greater than two) within the device.

Procedures

For delivery of some embodiments of the ocular implant, the implantationoccurs in a closed chamber with or without viscoelastic.

The implants may be placed using an applicator, such as a pusher, orthey may be placed using a delivery instrument having energy stored inthe instrument, such as disclosed in U.S. Patent Publication2004/0050392, filed Aug. 28, 2002, now U.S. Pat. No. 7,331,984, issuedFeb. 19, 2008, the entirety of which is incorporated herein by referenceand made a part of this specification and disclosure. In someembodiments, fluid may be infused through an applicator to create anelevated fluid pressure at the forward end of the implant to easeimplantation.

In one embodiment of the invention, a delivery apparatus (or“applicator”) similar to that used for placing a trabecular stentthrough a trabecular meshwork of an eye is used. Certain embodiments ofsuch a delivery apparatus are disclosed in U.S. Patent Publication2004/0050392, filed Aug. 28, 2002, now U.S. Pat. No. 7,331,984, issuedFeb. 19, 2008; U.S. Publication No.: 2002/0133168, entitled APPLICATORAND METHODS FOR PLACING A TRABECULAR SHUNT FOR GLAUCOMA TREATMENT, nowabandoned; and U.S. Provisional Application No. 60/276,609, filed Mar.16, 2001, entitled APPLICATOR AND METHODS FOR PLACING A TRABECULAR SHUNTFOR GLAUCOMA TREATMENT, now expired, each of which is incorporated byreference and made a part of this specification and disclosure.

The delivery apparatus includes a handpiece, an elongate tip, a holderand an actuator. The handpiece has a distal end and a proximal end. Theelongate tip is connected to the distal end of the handpiece. Theelongate tip has a distal portion and is configured to be placed througha corneal incision and into an anterior chamber of the eye. The holderis attached to the distal portion of the elongate tip. The holder isconfigured to hold and release the drug delivery implant. The actuatoris on the handpiece and actuates the holder to release the drug deliveryimplant from the holder. In one embodiment, a deployment mechanismwithin the delivery apparatus includes a push-pull type plunger.

In some embodiments, the holder comprises a clamp. In some embodiments,the apparatus further comprises a spring within the handpiece that isconfigured to be loaded when the drug delivery implant is being held bythe holder, the spring being at least partially unloaded upon actuatingthe actuator, allowing for release of the drug delivery implant from theholder.

In various embodiments, the clamp comprises a plurality of clawsconfigured to exert a clamping force onto at least the proximal portionof the drug delivery implant. The holder may also comprise a pluralityof flanges.

In some embodiments, the distal portion of the elongate tip is made of aflexible material. This can be a flexible wire. The distal portion canhave a deflection range, preferably of about 45 degrees from the longaxis of the handpiece. The delivery apparatus can further comprise anirrigation port in the elongate tip.

In some embodiments, the method includes using a delivery apparatus thatcomprises a handpiece having a distal end and a proximal end and anelongate tip connected to the distal end of the handpiece. The elongatetip has a distal portion and being configured to be placed through acorneal incision and into an anterior chamber of the eye. The apparatusfurther has a holder attached to the distal portion of the elongate tip,the holder being configured to hold and release the drug deliveryimplant, and an actuator on the handpiece that actuates the holder torelease the drug delivery implant from the holder.

The delivery instrument may be advanced through an insertion site in thecornea and advanced either transocularly or posteriorly into theanterior chamber, angle and positioned at base of the anterior chamberangle. Using the anterior chamber angle as a reference point, thedelivery instrument can be advanced further in a generally posteriordirection to drive the implant into the iris, inward of the anteriorchamber angle.

Optionally, based on the implant structure, the implant may be laidwithin the anterior chamber angle, taking on a curved shape to match theannular shape of the anterior chamber angle.

In some embodiments, the implant may be brought into position adjacentthe tissue in the anterior chamber angle or the iris tissue, and thepusher tube advanced axially toward the distal end of the deliveryinstrument. As the pusher tube is advanced, the implant is alsoadvanced. When the implant is advanced through the tissue and such thatit is no longer in the lumen of the delivery instrument, the deliveryinstrument is retracted, leaving the implant in the eye tissue.

The placement and implantation of the implant may be performed using agonioscope or other conventional imaging equipment. In some embodiments,the delivery instrument is used to force the implant into a desiredposition by application of a continual implantation force, by tappingthe implant into place using a distal portion of the deliveryinstrument, or by a combination of these methods. Once the implant is inthe desired position, it may be further seated by tapping using a distalportion of the delivery instrument.

In one embodiment, the drug delivery implant is affixed to an additionalportion of the iris or other intraocular tissue, to aid in fixating theimplant. In one embodiment, this additional affixation may be performedwith a biocompatible adhesive. In other embodiments, one or more suturesmay be used. In another embodiment, the drug delivery implant is heldsubstantially in place via the interaction of the implant body's outersurface and the surrounding tissue of the anterior chamber angle.

FIG. 23 illustrates one embodiment of a surgical method for implantingthe drug delivery implant into an eye, as described in the embodimentsherein. A first incision or slit is made through the conjunctiva and thesclera 11 at a location rearward of the limbus 21, that is, posterior tothe region of the sclera 11 at which the opaque white sclera 11 startsto become clear cornea 12. In some embodiments, the first incision isposterior to the limbus 21, including about 3 mm posterior to thelimbus. In some embodiments, the incision is made such that a surgicaltool may be inserted into the anterior chamber at a shallow angle(relative to the anteroposterior axis), as shown in FIG. 23. In otherembodiments, the first incision may be made to allow a larger angle ofinstrument insertion (see, e.g. FIGS. 24-26). Also, the first incisionis made slightly larger than the width of the drug delivery implant. Inone embodiment, a conventional cyclodialysis spatula may be insertedthrough the first incision into the supraciliary space to confirmcorrect anatomic position.

A portion of the upper and lower surfaces of the drug delivery implantcan be grasped securely by the surgical tool, for example, a forceps, sothat the forward end of the implant is oriented properly. The implantmay also be secured by viscoelastic or mechanical interlock with thepusher tube or wall of the implant delivery device. In one embodiment,the implant is oriented with a longitudinal axis of the implant beingsubstantially co-axial to a longitudinal axis of the grasping end of thesurgical tool. The drug delivery implant is disposed through the firstincision.

The delivery instrument may be advanced from the insertion sitetransocularly into the anterior chamber angle and positioned at alocation near the scleral spur. Using the scleral spur as a referencepoint, the delivery instrument can be advanced further in a generallyposterior direction to drive the implant into eye tissue at a locationjust inward of the scleral spur toward the iris.

Optionally, based on the implant structure, the shearing edge of theinsertion head of the implant can pass between the scleral spur and theciliary body 16 posterior to the trabecular meshwork.

The drug delivery implant may be continually advanced posteriorly untila portion of its insertion head and the first end of the conduit isdisposed within the anterior chamber 20 of the eye. Thus, the first endof the conduit is placed into fluid communication with the anteriorchamber 20 of the eye. The distal end of the elongate body of the drugdelivery implant can be disposed into the suprachoroidal space of theeye so that the second end of the conduit is placed into fluidcommunication with the suprachoroidal space. Alternatively, the implantmay be brought into position adjacent the tissue in the anterior chamberangle, and the pusher tube advanced axially toward the distal end of thedelivery instrument. As the pusher tube is advanced, the implant is alsoadvanced. When the implant is advanced through the tissue and such thatit is no longer in the lumen of the delivery instrument, the deliveryinstrument is retracted, leaving the implant in the eye tissue.

The placement and implantation of the implant may be performed using agonioscope or other conventional imaging equipment. In some embodiments,the delivery instrument is used to force the implant into a desiredposition by application of a continual implantation force, by tappingthe implant into place using a distal portion of the deliveryinstrument, or by a combination of these methods. Once the implant is inthe desired position, it may be further seated by tapping using a distalportion of the delivery instrument.

In one embodiment, the drug delivery implant is sutured to a portion ofthe sclera 11 to aid in fixating the implant. In one embodiment, thefirst incision is subsequently sutured closed. As one will appreciate,the suture used to fixate the drug delivery implant may also be used toclose the first incision. In another embodiment, the drug deliveryimplant is held substantially in place via the interaction of theimplant body's outer surface and the tissue of the sclera 11 and ciliarybody 16 and/or choroid 12 without suturing the implant to the sclera 11.Additionally, in one embodiment, the first incision is sufficientlysmall so that the incision self-seals upon withdrawal of the surgicaltool following implantation of the drug delivery implant withoutsuturing the incision.

As discussed herein, in some embodiments the drug delivery implantadditionally includes a shunt comprising a lumen configured provide adrainage device between the anterior chamber 20 and the suprachoroidalspace. Upon implantation, the drainage device may form a cyclodialysiswith the implant providing a permanent, patent communication of aqueoushumor through the shunt along its length. Aqueous humor is thusdelivered to the suprachoroidal space where it can be absorbed, andadditional reduction in pressure within the eye can be achieved.

In some embodiments it is desirable to deliver the drug delivery implantab interno across the eye, through a small incision at or near thelimbus (FIG. 24). The overall geometry of the system makes itadvantageous that the delivery instrument incorporates a distalcurvature, or a distal angle. In the former case, the drug deliveryimplant may be flexible to facilitate delivery along the curvature ormay be more loosely held to move easily along an accurate path. In thelatter case, the implant may be relatively rigid. The deliveryinstrument may incorporate an implant advancement element (e.g. pusher)that is flexible enough to pass through the distal angle.

In some embodiments, the implant and delivery instrument are advancedtogether through the anterior chamber 20 from an incision at or near thelimbus 21, across the iris 13, and through the ciliary muscle attachmentuntil the drug delivery implant outlet portion is located in theuveoscleral outflow pathway (e.g. exposed to the suprachoroidal spacedefined between the sclera 11 and the choroid 12). FIG. 24 illustrates atransocular implantation approach that may be used with the deliveryinstrument inserted well above the limbus 21. In other embodiments (see,e.g., FIG. 25), the incision may be made more posterior and closer tothe limbus 21. In one embodiment, the incision will be placed on thenasal side of the eye with the implanted location of the drug deliveryimplant 40 on the temporal side of the eye. In another embodiment, theincision may be made temporally such that the implanted location of thedrug delivery implant is on the nasal side of the eye. In someembodiments, the operator simultaneously pushes on a pusher device whilepulling back on the delivery instrument, such that the drug deliveryimplant outlet portion maintains its location in the posterior region ofthe suprachoroidal space near the macula 34, as illustrated in FIG. 26.The implant is released from the delivery instrument, and the deliveryinstrument retracted proximally. The delivery instrument is withdrawnfrom the anterior chamber through the incision.

In some embodiments, it is desirable to implant a drug delivery implantwith continuous aqueous outflow through the fibrous attachment zone,thus connecting the anterior chamber 20 to the uveoscleral outflowpathway, in order to reduce the intraocular pressure in glaucomatouspatients. In some embodiments, it is desirable to deliver the drugdelivery implant with a device that traverses the eye internally (abinterno), through a small incision in the limbus 21.

In several embodiments, microinvasive methods of implanting a drugdelivery implant are provided. In several such embodiments, an abexterno technique is utilized. In some embodiments, the technique isnon-penetrating, thereby limiting the invasiveness of the implantationmethod. As discussed herein, in some embodiments, the drug deliverydevice that is implanted comprises a shunt. In some embodiments, suchimplants facilitate removal of fluid from a first location, whilesimultaneously providing drug delivery. In some embodiments, theimplants communicate fluid from the anterior chamber to thesuprachoroidal space, which assists in removing fluid (e.g., aqueoushumor) from and reducing pressure increases in the anterior chamber.

In some embodiments (see e.g., FIG. 27), a window (e.g. a slit or othersmall incision) is surgically made through the conjunctiva and thesclera 11 to the surface of the choroid 28 (without penetration). Insome embodiments, the slit is made perpendicular to the optical axis ofthe eye. In some embodiments, a depth stop is used in conjunction withan incising device. In certain embodiments, the incising device is oneof a diamond or metal blade, a laser, or the like. In some embodiments,an initial incision is made with a sharp device, while the final portionof the incision to the choroid surface is made with a less sharpinstrument, thereby reducing risk of injury to the highly vascularchoroid. In some embodiments, the slit is created at or nearly at atangent to the sclera, in order to facilitate entry and manipulation ofan implant.

In some embodiments, a small core of sclera is removed at or near thepars plana, again, without penetration of the choroid. In order to avoidpenetration of the choroid, scleral thickness can optionally be measuredusing optical coherence tomography (OCT), ultrasound, or visual fixtureson the eye during the surgical process. In such embodiments, the scleralcore is removed by a trephining instrument (e.g., a rotary or statictrephintor) that optionally includes a depth stop gauge to ensure anincision to the proper depth. In other embodiments, a laser, diamondblade, metal blade, or other similar incising device is used.

After a window or slit is made in the sclera and the suprachoroidalspace is exposed, an implant 40 can be introduced into the window orslit and advanced in multiple directions through the use of aninstrument 38 a (see e.g., FIG. 27B-27C). Through the use of theinstrument 38 a, the implant 40 can be maneuvered in a posterior,anterior, superior, or inferior direction. The instrument 38 a isspecifically designed to advance the implant to the appropriate locationwithout harming the choroid or other structures. The instrument 38 a canthen be removed and the implant 40 left behind. In some embodiments, thewindow in the conjunctiva and sclera is small enough to be a selfsealing incision. In some embodiments, it can be a larger window or slitwhich can be sealed by means of a suture, staple, tissue common woundadhesive, or the like. A slit or window according to these embodimentscan be 1 mm or less in length or diameter, for example. In someembodiments, the length of the incision ranges from about 0.2 to about0.4 mm, about 0.4 to about 0.6 mm, about 0.6 mm to about 0.8 mm, about0.8 mm to about 1.0 mm, about 1.0 to about 1.5 mm, and overlappingranges thereof. In some embodiments larger incision (slit or window)dimensions are used.

In several embodiments, the implant 40 is tubular or oval tubular inshape. In some embodiments, such a shape facilitates passage of theimplant through the small opening. In some embodiments, the implant 40has a rounded closed distal end, while in other embodiments, the distalend is open. In several embodiments wherein open ended implants areused, the open end is filled (e.g., blocked temporarily) by a portion ofthe insertion instrument in order to prevent tissue plugging duringadvancement of the implant (e.g., into the suprachoroidal space). Inseveral embodiments, the implant is an implant as described herein andcomprises a lumen that contains a drug which elutes through holes,pores, or regions of drug release in the implant. As discussed herein,drug elution, in some embodiments, is targeted towards the posterior ofthe eye (e.g., the macula or optic nerve), and delivers therapeuticagents (e.g., steroids or anti VEGFs) to treat retinal or optic nervedisease.

In several embodiments, the implant 40 and implantation instrument 38 ais designed with an appropriate tip to allow the implant to be advancedin an anterior direction and penetrate into the anterior chamber withouta scleral cutdown. In some embodiments, the tip that penetrates into theanterior chamber is a part of the implant while in some embodiments, itis part of the insertion instrument. In such embodiments, the implantfunctions as a conduit for aqueous humor to pass from the anteriorchamber to the suprachoroidal space to treat glaucoma or ocularhypertension (e.g., a shunt). In several embodiments, the implant isconfigured to deliver a drug to the anterior chamber to treat glaucoma.In some embodiments, the drug is configured (e.g., produced) to eluteover a relatively long period of time (e.g., weeks to months or evenyears). Non-liming examples of such agents are beta blockers orprostaglandins. In some embodiments, a single implant is inserted, whilein other embodiments, two or more implants are implanted in this way, atthe same or different locations and in any combination of aqueous humorconduit or drug delivery mechanisms.

FIG. 28 shows an illustrative transocular method for placing any of thevarious implant embodiments taught or suggested herein at the implantsite within the eye 10. A delivery apparatus 100 b generally comprises asyringe portion 116 and a cannula portion 118. The distal section of thecannula 118 optionally has at least one irrigating hole 120 and a distalspace 122 for holding the drug delivery implant 30. The proximal end 124of the lumen of the distal space 122 is sealed from the remaining lumenof the cannula portion 118. The delivery apparatus of FIG. 28 may beemployed with the any of the various drug delivery implant embodimentstaught or suggested herein. In some embodiments, the target implant siteis the inferior portion of the iris. It should be understood that theangle of the delivery apparatus shown in FIG. 28 is illustrative, andangles more or less shallow than that shown may be preferable in someembodiments.

FIG. 29 shows an illustrative method for placing any of the variousimplant embodiments taught or suggested herein at implant site on thesame side of the eye. In one embodiment, the drug delivery implant isinserted into the anterior chamber 20 of the eye 10 to the iris with theaid of an applicator or delivery apparatus 100 c that creates a smallpuncture in the eye from the outside. In some embodiments, the targetimplant site is the inferior portion of the iris.

FIG. 30 illustrates a drug delivery implant consistent with severalembodiments disclosed herein affixed to the iris 13 of the eye 10consistent with several implantation methods disclosed herein. It shallbe appreciated that the iris is but one of many tissues that an implantas described here may be anchored to.

FIG. 31 illustrates another possible embodiment of placement of a drugdelivery implant consistent with several embodiments disclosed herein.In one embodiment, the outer shell 54 of an implant consistent withseveral embodiments disclosed herein is shown (in cross section)positioned in the anterior chamber angle. In one embodiment, thetransocular delivery method and apparatus may be used to position thedrug delivery implant wholly within the anterior chamber angle, whereinthe drug delivery implant substantially tracks the curvature of theanterior angle. In some embodiments, the implant is positionedsubstantially within the anterior chamber angle along the inferiorportion of the iris.

In some embodiments, the placement of the implant may result in the drugtarget being upstream of the natural flow of aqueous humor in the eye.For example, aqueous humor flows from the ciliary processes to theanterior chamber angle, which, based on the site of implantation incertain embodiments, may create a flow of fluid against which a drugreleased from an implant may have to travel in order to make contactwith a target tissue. Thus, in certain embodiments, for example when thetarget tissue is the ciliary processes, eluted drug must diffuse throughiris tissue to get from the anterior chamber to target receptors in theciliary processes in the posterior chamber. The requirement fordiffusion of drug through the iris, and the flow of the aqueous humor,in certain instances, may limit the amount of eluted drug reaching theciliary body.

To overcome these issues, certain embodiments involve placement of aperipheral iridotomy (PI), or device-stented PI, at a location adjacentto a drug eluting implant to facilitate delivery of a drug directly tothe intended site of action (i.e., the target tissue). The creation of aP opens a relatively large communication passage between the posteriorand anterior chambers. While a net flow of aqueous humor from theposterior chamber to the anterior chamber still exists, the relativelylarge diameter of the PI substantially reduces the linear flow velocity.Thus, eluted drug is able to diffuse through the PI without significantopposition from flow of aqueous humor. In certain such embodiments, aportion of the implant is structured to penetrate the iris and elute thedrug directly into the posterior chamber at the ciliary body. In otherembodiments, the implant is implanted and/or anchored in the iris andelutes drug directly to the posterior chamber and adjacent ciliary body.

FIG. 22 shows a meridional section of the anterior segment of the humaneye and schematically illustrates another embodiment of a deliveryinstrument 38 that may be used with embodiments of drug deliveryimplants described herein. In FIG. 22, arrows 82 show the fibrousattachment zone of the ciliary muscle 84 to the sclera 11. The ciliarymuscle 84 is coextensive with the choroid 28. The suprachoroidal spaceis the interface between the choroid 28 and the sclera 11. Otherstructures in the eye include the lens 26, the cornea 12, the anteriorchamber 20, the iris 13, and Schlemm's canal 22.

The delivery instrument/implant assembly can be passed between the iris13 and the cornea 12 to reach the iridocorneal angle. Therefore, theheight of the delivery instrument/shunt assembly (dimension 90 in FIG.22) is less than about 3 mm in some embodiments, and less than 2 mm inother embodiments.

The suprachoroidal space between the choroid 28 and the sclera 11generally forms an angle 96 of about 55° with the optical axis 98 of theeye. This angle, in addition to the height requirement described in thepreceding paragraph, are features to consider in the geometrical designof the delivery instrument/implant assembly.

The overall geometry of the drug delivery implant system makes itadvantageous that the delivery instrument 38 incorporates a distalcurvature 86, as shown in FIG. 22, a distal angle 88, as shown in FIG.21, or a combination thereof. The distal curvature (FIG. 23) is expectedto pass more smoothly through the corneal or scleral incision at thelimbus. In this embodiment, the drug delivery implant may be curved orflexible. Alternatively, in the design of FIG. 21, the drug deliveryimplant may be mounted on the straight segment of the deliveryinstrument, distal of the “elbow” or angle 88. In this case, the drugdelivery implant may be straight and relatively inflexible, and thedelivery instrument may incorporate a delivery mechanism that isflexible enough to advance through the angle. In some embodiments, thedrug delivery implant may be a rigid tube, provided that the implant isno longer than the length of the distal segment 92.

The distal curvature 86 of delivery instrument 38 may be characterizedas a radius of between about 10 to 30 mm in some embodiments, and about20 mm in certain embodiments. The distal angle of the deliveryinstrument in an embodiment as depicted in FIG. 21 may be characterizedas between about 90 to 170 degrees relative to an axis of the proximalsegment 94 of the delivery instrument. In other embodiments, the anglemay be between about 145 and about 170 degrees. The angle incorporates asmall radius of curvature at the “elbow” so as to make a smoothtransition from the proximal segment 94 of the delivery instrument tothe distal segment 92. The length of the distal segment 92 may beapproximately 0.5 to 7 mm in some embodiments, and about 2 to 3 mm incertain embodiments.

In some embodiments, a viscoelastic, or other fluid is injected into thesuprachoroidal space to create a chamber or pocket between the choroidand sclera which can be accessed by a drug delivery implant. Such apocket exposes more of the choroidal and scleral tissue area, provideslubrication and protection for tissues during implantation, andincreases uveoscleral outflow in embodiments where the drug deliveryimplant includes a shunt, causing a lower intraocular pressure (IOP). Insome embodiments, the viscoelastic material is injected with a 25 or 27Gcannula, for example, through an incision in the ciliary muscleattachment or through the sclera (e.g. from outside the eye). Theviscoelastic material may also be injected through the implant itselfeither before, during or after implantation is completed.

In some embodiments, a hyperosmotic agent is injected into thesuprachoroidal space. Such an injection can delay IOP reduction. Thus,hypotony may be avoided in the acute postoperative period by temporarilyreducing choroidal absorption. The hyperosmotic agent may be, forexample glucose, albumin, HYPAQUE™ medium, glycerol, or poly(ethyleneglycol). The hyperosmotic agent can breakdown or wash out as the patientheals, resulting in a stable, acceptably low IOP, and avoiding transienthypotony.

Controlled Drug Release

The drug delivery implants as described herein, function to house a drugand provide drug elution from the implant in a controlled fashion, basedon the design of the various components of the implant, for an extendedperiod of time. Various elements of the implant composition, implantphysical characteristics, implant location in the eye, and thecomposition of the drug work in combination to produce the desired drugrelease profile.

As described above the drug delivery implant may be made from anybiological inert and biocompatible materials having desiredcharacteristics. Desirable characteristics, in some embodiments, includepermeability to liquid water or water vapor, allowing for an implant tobe manufactured, loaded with drug, and sterilized in a dry state, withsubsequent rehydration of the drug upon implantation. Also desirable isan implant constructed of a material comprising microscopic porositiesbetween polymer chains. These porosities may interconnect, which formschannels of water through the implant material. In several embodiments,the resultant channels are convoluted and thereby form a tortuous pathwhich solublized drug travels during the elution process. Implantmaterials advantageously also possess sufficient permeability to a drugsuch that the implant may be a practical size for implantation. Thus, inseveral embodiments, the implant material is sufficiently permeable tothe drug to be delivered that the implant is dimensioned to residewholly contained within the eye of a subject. Implant material alsoideally possesses sufficient elasticity, flexibility and potentialelongation to not only conform to the target anatomy during and afterimplantation, but also remain unkinked, untorn, unpunctured, and with apatent lumen during and after implantation. In several embodiments,implant material would advantageously processable in a practical manner,such as, for example, by molding, extrusion, thermoforming, and thelike.

Illustrative, examples of suitable materials for the outer shell includepolypropylene, polyimide, glass, nitinol, polyvinyl alcohol, polyvinylpyrolidone, collagen, chemically-treated collagen, polyethersulfone(PES), poly(styrene-isobutyl-styrene), polyurethane, ethyl vinyl acetate(EVA), polyetherether ketone (PEEK), Kynar (Polyvinylidene Fluoride;PVDF), Polytetrafluoroethylene (PTFE), Polymethylmethacrylate (PMMA),Pebax, acrylic, polyolefin, polydimethylsiloxane and other siliconeelastomers, polypropylene, hydroxyapetite, titanium, gold, silver,platinum, other metals and alloys, ceramics, plastics and mixtures orcombinations thereof. Additional suitable materials used to constructcertain embodiments of the implant include, but are not limited to,poly(lactic acid), poly(tyrosine carbonate), polyethylene-vinyl acetate,poly(L-lactic acid), poly(D,L-lactic-co-glycolic acid),poly(D,L-lactide), poly(D,L-lactide-co-trimethylene carbonate),collagen, heparinized collagen, poly(caprolactone), poly(glycolic acid),and/or other polymer, copolymers, or block co-polymers, polyesterurethanes, polyester amides, polyester ureas, polythioesters,thermoplastic polyurethanes, silicone-modified polyether urethanes,poly(carbonate urethane), or polyimide. Thermoplastic polyurethanes arepolymers or copolymers which may comprise aliphatic polyurethanes,aromatic polyurethanes, polyurethane hydrogel-forming materials,hydrophilic polyurethanes (such as those described in U.S. Pat. No.5,428,123, which is incorporated in its entirety by reference herein),or combinations thereof. Non-limiting examples include elasthane(poly(ether urethane)) such as Elasthane™ 80A, Lubrizol, Tecophilic™,Pellethane™, Carbothane™, Tecothane™, Tecoplast™, and Estane™. In someembodiments, polysiloxane-containing polyurethane elastomers are used,which include Carbosil™ 20 or Pursil™ 20 80A, Elast-Eon™, and the like.Hydrophilic and/or hydrophobic materials may be used. Non-limitingexamples of such elastomers are provided in U.S. Pat. No. 6,627,724,which is incorporated in its entirety by reference herein.Poly(carbonate urethane) may include Bionate™ 80A or similar polymers.In several embodiments, such silicone modified polyether urethanes areparticularly advantageous based on improved biostability of the polymerimparted by the inclusion of silicone. In addition, in some embodiments,oxidative stability and thrombo-resistance is also improved as comparedto non-modified polyurethanes. In some embodiments, there is a reductionin angiogenesis, cellular adhesion, inflammation, and/or proteinadsorption with silicone-modified polyether urethanes. In otherembodiments, should angiogenesis, cellular adhesion or proteinadsorption (e.g., for assistance in anchoring an implant) be preferable,the degree of silicone (or other modifier) may be adjusted accordingly.Moreover, in some embodiments, silicone modification reduces thecoefficient of friction of the polymer, which reduces trauma duringimplantation of devices described herein. In some embodiments, siliconemodification, in addition to the other mechanisms described herein, isanother variable that can be used to tailor the permeability of thepolymer. Further, in some embodiments, silicone modification of apolymer is accomplished through the addition of silicone-containingsurface modifying endgroups to the base polymer. In other embodiments,flurorocarbon or polyethylene oxide surface modifying endgroups areadded to a based polymer. In several embodiments, one or morebiodegradable materials are used to construct all or a portion of theimplant, or any other device disclosed herein. Such materials includeany suitable material that degrades or erodes over time when placed inthe human or animal body, whether due to a particular chemical reactionor enzymatic process or in the absence of such a reaction or process.Accordingly, as the terms is used herein, biodegradable materialincludes bioerodible materials. In such biodegradable embodiments, thedegradation rate of the biodegradable outer shell is another variable(of many) that may be used to tailor the drug elution rate from animplant.

In some embodiments, such as where the drug is sensitive to moisture(e.g. liquid water, water vapor, humidity) or where the drug's long termstability may be adversely affected by exposure to moisture, it may bedesirable to utilize a material for the implant or at least a portion ofthe implant, which is water resistant, water impermeable or waterproofsuch that it presents a significant barrier to the intrusion of liquidwater and/or water vapor, especially at or around human body temperature(e.g. about 35-40° C. or 37° C.). This may be accomplished by using amaterial that is, itself, water resistant, water impermeable orwaterproof.

In some circumstances, however, even materials that are generallyconsidered water impermeable may still allow in enough water toadversely affect the drug within an implant. For example, it may bedesirable to have 5% by weight of the drug or less water intrusion overthe course of a year. In one embodiment of implant, this would equate toa water vapor transmission rate for a material of about 1×10⁻³ g/m²/dayor less. This may be as much as one-tenth of the water transmission rateof some polymers generally considered to be water resistant or waterimpermeable. Therefore, it may be desirable to increase the waterresistance or water impermeability of a material.

The water resistance or water impermeability of a material may beincreased by any suitable method. Such methods of treatment includeproviding a coating for a material (including by lamination) or bycompounding a material with a component that adds water resistance orincreases impermeability. For example, such treatment may be performedon the implant (or portion of the implant) itself, it may be done on thematerial prior to fabrication (e.g. coating a polymeric tube), or it maybe done in the formation of the material itself (e.g. by compounding aresin with a material prior to forming the resin into a tube or sheet).Such treatment may include, without limitation, one or more of thefollowing: coating or laminating the material with a hydrophobic polymeror other material to increase water resistance or impermeability;compounding the material with hydrophobic or other material to increasewater resistance or impermeability; compounding or treating the materialwith a substance that fills microscopic gaps or pores within thematerial that allow for ingress of water or water vapor, coating and/orcompounding the material with a water scavenger or hygroscopic materialthat can absorb, adsorb or react with water so as to increase the waterresistance or impermeability of the material.

One type of material that may be employed as a coating to increase waterresistance and/or water impermeability is an inorganic material.Inorganic materials include, but are not limited to, metals, metaloxides and other metal compounds (e.g. metal sulfides, metal hydrides),ceramics, and main group materials and their compounds (e.g. carbon(e.g. carbon nanotubes), silicon, silicon oxides). Examples of suitablematerials include aluminum oxides (e.g Al₂O₃) and silicon oxides (e.g.SiO₂). Inorganic materials may be advantageously coated onto a material(at any stage of manufacture of the material or implant) usingtechniques such as are known in the art to create extremely thincoatings on a substrate, including by vapor deposition, atomic layerdeposition, plasma deposition, and the like. Such techniques can providefor the deposition of very thin coatings (e.g about 20 nm-40 nm thick,including about 25 nm thick, about 30 nm thick, and about 35 nm thick)on substrates, including polymeric substrates, and can provide a coatingon the exterior and/or interior luminal surfaces of small tubing,including that of the size suitable for use in implants disclosedherein. Such coatings can provide excellent resistance to the permeationof water or water vapor while still being at least moderately flexibleso as not to undesirably compromise the performance of an implant inwhich flexibility is desired.

In order to control the dose or duration of treatment, in embodimentswherein the therapeutic agents are delivered via flexible tetheredimplants (see, e.g., FIGS. 16-17), one or more flexible sheets or discsmay be simultaneously used. Similarly the material used to construct thesheets or discs and/or the coatings covering them may be prepared tocontrol the rate of release of the drug, similar to as discussed below.

The drugs carried by the drug delivery implant may be in any form thatcan be reasonably retained within the device and results in controlledelution of the resident drug or drugs over a period of time lasting atleast several days and in some embodiments up to several weeks, and incertain preferred embodiments, up to several years. Certain embodimentsutilize drugs that are readily soluble in ocular fluid, while otherembodiments utilize drugs that are partially soluble in ocular fluid.

For example, the therapeutic agent may be in any form, including but notlimited to a compressed pellet, a solid, a capsule, multiple particles,a liquid, a gel, a suspension, slurry, emulsion, and the like. Incertain embodiments, drug particles are in the form of micro-pellets(e.g., micro-tablets), fine powders, or slurries, each of which havefluid-like properties, allowing for recharging by injection into theinner lumen(s). As discussed above, in some embodiments, the loadingand/or recharging of a device is accomplished with a syringe/needle,through which the therapeutic agent is delivered. In some embodiments,micro-tablets are delivered through a needle of about 23 gauge to about32 gauge, including 23-25 gauge, 25 to 27 gauge, 27-29 gauge, 29-30gauge, 30-32 gauge, and overlapping ranges thereof. In some embodiments,the needle is 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 gauge.

When more than one drug is desired for treatment of a particularpathology or when a second drug is administered such as to counteract aside effect of the first drug, some embodiments may utilize two agentsof the same form. In other embodiments, agents in different form may beused. Likewise, should one or more drugs utilize an adjuvant, excipient,or auxiliary compound, for example to enhance stability or tailor theelution profile, that compound or compounds may also be in any form thatis compatible with the drug and can be reasonably retained with theimplant.

In some embodiments, treatment of particular pathology with a drugreleased from the implant may not only treat the pathology, but alsoinduce certain undesirable side effects. In some cases, delivery ofcertain drugs may treat a pathological condition, but indirectlyincrease intraocular pressure. Steroids, for example, may have such aneffect. In certain embodiments, a drug delivery shunt delivers a steroidto an ocular target tissue, such as the retina or other target tissue asdescribed herein, thereby treating a retinal pathology but also possiblyinducing increased intraocular pressure which may be due to localinflammation or fluid accumulation. In such embodiments, the shuntfeature reduces undesirable increased intraocular pressure bytransporting away the accumulated fluid. Thus, in some embodiments,implants functioning both as drug delivery devices and shunts can notonly serve to deliver a therapeutic agent, but simultaneously drain awayaccumulated fluid, thereby alleviating the side effect of the drug. Suchembodiments can be deployed in an ocular setting, or in any otherphysiological setting where delivery of a drug coordinately causes fluidaccumulation which needs to be reduced by the shunt feature of theimplant. In some such embodiments, drainage of the accumulated fluid isnecessary to avoid tissue damage or loss of function, in particular whenthe target tissue is pressure sensitive or has a limited space orcapacity to expand in response to the accumulated fluid. The eye and thebrain are two non-limiting examples of such tissues.

It will be understood that embodiments as described herein may include adrug mixed or compounded with a biodegradable material, excipient, orother agent modifying the release characteristics of the drug. Preferredbiodegradable materials include copolymers of lactic acid and glycolicacid, also known as poly (lactic-co-glycolic acid) or PLGA. It will beunderstood by one skilled in the art that although some disclosureherein specifically describes use of PLGA, other suitable biodegradablematerials may be substituted for PLGA or used in combination with PLGAin such embodiments. It will also be understood that in certainembodiments as described herein, the drug positioned within the lumen ofthe implant is not compounded or mixed with any other compound ormaterial, thereby maximizing the volume of drug that is positionedwithin the lumen.

It may be desirable, in some embodiments, to provide for a particularrate of release of drug from a PLGA copolymer or other polymericmaterial. As the release rate of a drug from a polymer correlates withthe degradation rate of that polymer, control of the degradation rateprovides a means for control of the delivery rate of the drug containedwithin the therapeutic agent. Variation of the average molecular weightof the polymer or copolymer chains which make up the PLGA copolymer orother polymer may be used to control the degradation rate of thecopolymer, thereby achieving a desired duration or other release profileof therapeutic agent delivery to the eye.

In certain other embodiments employing PLGA copolymers, rate ofbiodegradation of the PLGA copolymer may be controlled by varying theratio of lactic acid to glycolic acid units in a copolymer.

Still other embodiments may utilize combinations of varying the averagemolecular weights of the constituents of the copolymer and varying theratio of lactic acid to glycolic acid in the copolymer to achieve adesired biodegradation rate.

As described above, the outer shell of the implant comprises a polymerin some embodiments. Additionally, the shell may further comprise one ormore polymeric coatings in various locations on or within the implant.The outer shell and any polymeric coatings are optionally biodegradable.The biodegradable outer shell and biodegradable polymer coating may beany suitable material including, but not limited to, poly(lactic acid),polyethylene-vinyl acetate, poly(lactic-co-glycolic acid),poly(D,L-lactide), poly(D,L-lactide-co-trimethylene carbonate),collagen, heparinized collagen, poly(caprolactone), poly(glycolic acid),and/or other polymer or copolymer.

As described above, some embodiments of the implants comprise apolymeric outer shell that is permeable to ocular fluids in a controlledfashion depending on the constituents used in forming the shell. Forexample, the concentration of the polymeric subunits dictates thepermeability of the resulting shell. Therefore, the composition of thepolymers making up the polymeric shell determines the rate of ocularfluid passage through the polymer and if biodegradable, the rate ofbiodegradation in ocular fluid. The permeability of the shell will alsoimpact the release of the drug from the shell. Also as described above,the regions of drug release created on the shell will alter the releaseprofile of a drug from the implant. Control of the release of the drugcan further be controlled by coatings in or on the shell that eitherform the regions of drug release, or alter the characteristics of theregions of drug release (e.g., a coating over the region of drug releasemakes the region thicker, and therefore slows the rate of release of adrug).

For example, a given combination of drug and polymer will yield acharacteristic diffusion coefficient D, such that:

${{Elution}\mspace{14mu} {rate}} = \frac{\left\lbrack {D \times A \times \left( {C_{i} - C_{o}} \right)} \right\rbrack}{d}$

where D=diffusion coefficient (cm²/sec)

-   -   A=area of the region of drug release    -   (Ci−Co)=difference in drug concentration between the inside and        outside of the device.    -   d=thickness of the region of drug release

Thus, the area and thickness of the region of drug release are variablesthat determine, in part, the rate of elution of the drug from theimplant, and are also variable that can be controlled during the processof manufacturing the implant. In some embodiments using a highlyinsoluble drug, the region of drug release could be manufactured to bethin (d is small) or with a large overall area (A is large) or acombination of the two (as dictated by the structural sufficiency of theouter shell). In either case, the end result is that the elution rate ofthe drug can be increased to compensate for the low solubility of thedrug based on the structure and design of the implant.

In contrast, in some embodiments using a highly soluble drug, theregions of drug release are made of substantially the same thickness asthe remainder of the outer shell, made of small area, or combinationsthereof.

Additionally, certain embodiments use additional polymer coatings toeither (i) increase the effective thickness (d) of the region of drugrelease or (ii) decrease the overall permeability of the of that portionof the implant (region of drug release plus the coating), resulting in areduction in drug elution. In still other embodiments, multipleadditional polymer coatings are used. By covering either distinct oroverlapping portions of the implant and the associated regions of drugrelease on the outer shell, drug release from various regions of theimplant are controlled and result in a controlled pattern of drugrelease from the implant overall. For example, an implant with at leasttwo regions of drug release may be coated with two additional polymers,wherein the additional polymers both cover over region of release andonly a single polymer covers the other region. Thus the elution rate ofdrug from the two regions of drug release differ, and are controllablesuch that, for example, drug is released sequentially from the tworegions. In other embodiments, the two regions may release at differentrates. In those embodiments with multiple interior lumens, differentconcentrations or different drugs may also be released. It will beappreciated that these variables are controllable to alter to rate orduration of drug release from the implant such that a desired elutionprofile or treatment regimen can be created.

In several embodiments as described herein, there are no direct throughholes or penetrating apertures needed or utilized to specificallyfacilitate or control drug elution. As such, in those embodiments, thereis no direct contact between the drug core (which may be of very highconcentration) and the ocular tissue where adjacent to the site wherethe implant is positioned. In some cases, direct contact of oculartissue with high concentrations of drug residing within the implantcould lead to local cell toxicity and possible local cell death.

It shall however, be appreciated that, in several other embodiments,disclosed herein, that the number, size, and placement of one or moreorifices through the outer shell of the implant may be altered in orderto produce a desired drug elution profile. As the number, size, or both,of the orifices increases relative to surface area of the implant,increasing amounts of ocular fluid pass across the outer shell andcontact the therapeutic agent on the interior of the implant. Likewise,decreasing the ratio of orifice:outer shell area, less ocular fluid willenter the implant, thereby providing a decreased rate of release of drugfrom the implant. Additionally, multiple orifices provides a redundantcommunication means between the ocular environment that the implant isimplanted in and the interior of the implant, should one or moreorifices become blocked during implantation or after residing in theeye. In other embodiments, the outer shell may contain one (or more)orifice(s) in the distal tip of the implant. As described above, theshape and size of this orifice is selected based on the desired elutionprofile. In some embodiments, a biodegradable polymer plug is positionedwithin the distal orifice, thereby acting as a synthetic cork. Tissuetrauma or coring of the ocular tissue during the process of implantationis also reduced, which may prevent plugging or partial occlusion of thedistal orifice. Additionally, because the polymer plug may be tailoredto biodegrade in a known time period, the plug ensures that the implantcan be fully positioned before any elution of the drug takes place.Still other embodiments comprise a combination of a distal orifice andmultiple orifices placed more proximally on the outer shell, asdescribed above.

Moreover, the addition of one or more permeable or semi-permeablecoatings on an implant (either with orifices or regions of drug release)may also be used to tailor the elution profile. Additionally,combinations of these various elements may be used in some embodimentsto provide multiple methods of controlling the drug release profile.

Further benefiting the embodiments described herein is the expandedpossible range of uses for some ocular therapy drugs. For example, adrug that is highly soluble in ocular fluid may have narrowapplicability in treatment regimes, as its efficacy is limited to thosepathologies treatable with acute drug administration. However, whencoupled with the implants as disclosed herein, such a drug could beutilized in a long term therapeutic regime. A highly soluble drugpositioned within the distal portion of the implant containing one ormore regions of drug release may be made to yield a particular,long-term controlled release profile.

Alternatively, or in addition to one or more regions of drug release,one or more polymeric coatings may be located outside the implant shell,or within the interior lumen, enveloping or partially enveloping thedrug. In some embodiments comprising one or more orifices, the polymericcoating is the first portion of the implant in contact with ocularfluid, and thus, is a primary controller of the rate of entry of ocularfluid into the drug containing interior lumen of the implant. Byaltering the composition of the polymer coating, the biodegradation rate(if biodegradable), and porosity of the polymer coating the rate atwhich the drug is exposed to and solublized in the ocular fluid may becontrolled. Thus, there is a high degree of control over the rate atwhich the drug is released from such an embodiment of an implant to thetarget tissue of the eye. Similarly, a drug with a low ocular fluidsolubility may be positioned within an implant coated with a rapidlybiodegradable or highly porous polymer coating, allowing increased flowof ocular fluid over the drug within the implant.

In certain embodiments described herein, the polymer coating envelopesthe therapeutic agent within the lumen of the implant. In some suchembodiments, the ocular fluid passes through the outer shell of theimplant and contacts the polymer layer. Such embodiments may beparticularly useful when the implant comprises one or more orificesand/or the drug to be delivered is a liquid, slurry, emulsion, orparticles, as the polymer layer would not only provide control of theelution of the drug, but would assist in providing a structural barrierto prevent uncontrolled leakage or loss of the drug outwardly throughthe orifices. The interior positioning of the polymer layer could,however, also be used in implants where the drug is in any form.

In some ocular disorders, therapy may require a defined kinetic profileof administration of drug to the eye. It will be appreciated from theabove discussion of various embodiments that the ability to tailor therelease rate of a drug from the implant can similarly be used toaccomplish achieve a desired kinetic profile. For example thecomposition of the outer shell and any polymer coatings can bemanipulated to provide a particular kinetic profile of release of thedrug. Additionally, the design of the implant itself, including thethickness of the shell material, the thickness of the shell in theregions of drug release, the area of the regions of drug release, andthe area and/or number of any orifices in the shell provide a means tocreate a particular drug release profile. Likewise, the use of PLGAcopolymers and/or other controlled release materials and excipients, mayprovide particular kinetic profiles of release of the compounded drug.By tailoring the ratio of lactic to glycolic acid in a copolymer and/oraverage molecular weight of polymers or copolymers having the drugtherein (optionally with one or more other excipients), sustainedrelease of a drug, or other desirable release profile, may be achieved.

In certain embodiments, zero-order release of a drug may be achieved bymanipulating any of the features and/or variables discussed above aloneor in combination so that the characteristics of the implant are theprincipal factor controlling drug release from the implant. Similarly,in those embodiments employing PLGA compounded with the drug, tailoringthe ratio of lactic to glycolic acid and/or average molecular weights inthe copolymer-drug composition can adjust the release kinetics based onthe combination of the implant structure and the biodegradation of thePLGA copolymer.

In other embodiments, pseudo zero-order release (or other desiredrelease profile) may be achieved through the adjustment of thecomposition of the implant shell, the structure and dimension of theregions of drug release, the composition any polymer coatings, and useof certain excipients or compounded formulations (PLGA copolymers), theadditive effect over time replicating true zero-order kinetics.

For example, in one embodiment, an implant with a polymer coatingallowing entry of ocular fluid into the implant at a known rate maycontain a series of pellets that compound PLGA with one or more drugs,wherein the pellets incorporate at least two different PLGA copolymerformulations. Based on the formulation of the first therapeutic agent,each subsequent agent may be compounded with PLGA in a manner as toallow a known quantity of drug to be released in a given unit of time.As each copolymer biodegrades or erodes at its individual and desiredrate, the sum total of drug released to the eye over time is in effectreleased with zero-order kinetics. It will be appreciated thatembodiments additionally employing the drug partitions as describedherein, operating in conjunction with pellets having multiple PLGAformulations would add an additional level of control over the resultingrate of release and kinetic profile of the drug.

Non-continuous or pulsatile release may also be desirable. This may beachieved, for example, by manufacturing an implant with multiplesub-lumens, each associated with one or more regions of drug release. Insome embodiments, additional polymer coatings are used to prevent drugrelease from certain regions of drug release at a given time, while drugis eluted from other regions of drug release at that time. Otherembodiments additionally employ one or more biodegradable partitions asdescribed above to provide permanent or temporary physical barrierswithin an implant to further tune the amplitude or duration of period oflowered or non-release of drug from the implant. Additionally, bycontrolling the biodegradation rate of the partition, the length of adrug holiday may be controlled. In some embodiments the biodegradationof the partition may be initiated or enhanced by an external stimulus.In some embodiments, the intraocular injection of a fluid stimulates orenhances biodegradation of the barrier. In some embodiments, theexternally originating stimulus is one or more of application of heat,ultrasound, and radio frequency, or laser energy.

Certain embodiments are particularly advantageous as the regions of drugrelease minimize tissue trauma or coring of the ocular tissue during theprocess of implantation, as they are not open orifices. Additionally,because the regions are of a known thickness and area (and therefore ofa known drug release profile) they can optionally be manufactured toensure that the implant can be fully positioned before any elution ofthe drug takes place.

Placement of the drug within the interior of the outer shell may also beused as a mechanism to control drug release. In some embodiments, thelumen may be in a distal position, while in others it may be in a moreproximal position, depending on the pathology to be treated. In thoseembodiments employing a nested or concentric tube device, the agent oragents may be placed within any of the lumens formed between the nestedor concentric polymeric shells

Further control over drug release is obtained by the placement locationof drug in particular embodiments with multiple lumens. For example,when release of the drug is desired soon after implantation, the drug isplaced within the implant in a first releasing lumen having a short timeperiod between implantation and exposure of the therapeutic agent toocular fluid. This is accomplished, for example by juxtaposing the firstreleasing lumen with a region of drug release having a thin outer shellthickness (or a large area, or both). A second agent, placed in a secondreleasing lumen with a longer time to ocular fluid exposure elutes druginto the eye after initiation of release of the first drug. This can beaccomplished by juxtaposing the second releasing lumen with a region ofdrug release having a thicker shell or a smaller area (or both).Optionally, this second drug treats side effects caused by the releaseand activity of the first drug.

It will also be appreciated that the multiple lumens as described aboveare also useful in achieving a particular concentration profile ofreleased drug. For example, in some embodiments, a first releasing lumenmay contain a drug with a first concentration of drug and a secondreleasing lumen containing the same drug with a different concentration.The desired concentration profile may be tailored by the utilizing drugshaving different drug concentration and placing them within the implantin such a way that the time to inception of drug elution, and thusconcentration in ocular tissues, is controlled.

Further, placement location of the drug may be used to achieve periodsof drug release followed by periods of no drug release. By way ofexample, a drug may be placed in a first releasing lumen such that thedrug is released into the eye soon after implantation. A secondreleasing lumen may remain free of drug, or contain an inert bioerodiblesubstance, yielding a period of time wherein no drug is released. Athird releasing lumen containing drug could then be exposed to ocularfluids, thus starting a second period of drug release.

It will be appreciated that the ability to alter any one of orcombination of the shell characteristics, the characteristics of anypolymer coatings, any polymer-drug admixtures, the dimension and numberof regions of drug release, the dimension and number of orifices, andthe position of drugs within the implant provides a vast degree offlexibility in controlling the rate of drug delivery by the implant.

The drug elution profile may also be controlled by the utilization ofmultiple drugs contained within the same interior lumen of the implantthat are separated by one or more plugs. By way of example, in animplant comprising a single region of drug release in the distal tip ofthe implant, ocular fluid entering the implant primarily contacts thedistal-most drug until a point in time when the distal-most drug issubstantially eroded and eluted. During that time, ocular fluid passesthrough a first semi-permeable partition and begins to erode a seconddrug, located proximal to the plug. As discussed below, the compositionof these first two drugs, and the first plug, as well as thecharacteristics of the region of drug release may each be controlled toyield an overall desired elution profile, such as an increasingconcentration over time or time-dependent delivery of two differentdoses of drug. Different drugs may also be deployed sequentially with asimilar implant embodiment.

Partitions may be used if separation of two drugs is desirable. Apartition is optionally biodegradable at a rate equal to or slower thanthat of the drugs to be delivered by the implant. The partitions aredesigned for the interior dimensions of a given implant embodiment suchthat the partition, when in place within the interior lumen of theimplant, will seal off the more proximal portion of the lumen from thedistal portion of the lumen. The partitions thus create individualcompartments within the interior lumen. A first drug may be placed inthe more proximal compartment, while a second drug, or a secondconcentration of the first drug, or an adjuvant agent may be placed inthe more distal compartment. As described above, the entry of ocularfluid and rate of drug release is thus controllable and drugs can bereleased in tandem, in sequence or in a staggered fashion over time.

Partitions may also be used to create separate compartments fortherapeutic agents or compounds that may react with one another, butwhose reaction is desired at or near ocular tissue, not simply withinthe implant lumen. As a practical example, if each of two compounds wasinactive until in the presence of the other (e.g. a prodrug and amodifier), these two compounds may still be delivered in a singleimplant having at least one region of drug release associated only withone drug-containing lumen. After the elution of the compounds from theimplant to the ocular space the compounds would comingle, becomingactive in close proximity to the target tissue. As can be determinedfrom the above description, if more than two drugs are to be deliveredin this manner, utilizing an appropriately increased number ofpartitions to segregate the drugs would be desirable.

In certain embodiments, a proximal barrier serves to seal thetherapeutic agent within a distally located interior lumen of theimplant. The purpose of such a barrier is to ensure that the ocularfluid from any more distally located points of ocular fluid entry is theprimary source of ocular fluid contacting the therapeutic agent.Likewise, a drug impermeable seal is formed that prevents the elution ofdrug in an anterior direction. Prevention of anterior elution not onlyprevents dilution of the drug by ocular fluid originating from ananterior portion of the eye, but also reduces potential side of effectsof drugs delivered by the device. Limiting the elution of the drug tosites originating in the distal region of the implant will enhance thedelivery of the drug to the target sites in more posterior regions ofthe eye. In embodiments that are fully biodegradable, the proximal capor barrier may comprise a biocompatible biodegradable polymer,characterized by a biodegradation rate slower than all the drugs to bedelivered by that implant. It will be appreciated that the proximal capis useful in those embodiments having a single central lumen running thelength of the implant to allow recharging the implant after the firstdose of drug has fully eluted. In those embodiments, the single centrallumen is present to allow a new drug to be placed within the distalportion of the device, but is preferably sealed off at or near theproximal end to avoid anteriorly directed drug dilution or elution.

Similar to the multiple longitudinally located compartments that may beformed in an implant, drugs may also be positioned within one or morelumens nested within one another. By ordering particularly desirabledrugs or concentrations of drugs in nested lumens, one may achievesimilarly controlled release or kinetic profiles as described above.

Wicks, as described above, may also be employed to control the releasecharacteristics of different drugs within the implant. One or more wicksleading into separate interior lumens of an implant assist in movingocular fluid rapidly into the lumen where it may interact with the drug.Drugs requiring more ocular fluid for their release may optionally bepositioned in a lumen where a wick brings in more ocular fluid than anorifice alone would allow. One or more wicks may be used in someembodiments.

In some embodiments, drugs are variably dimensioned to further tailorthe release profile by increasing or limiting ocular fluid flow into thespace in between the drug and walls of the interior lumen. For example,if it was optimal to have a first solid or semi solid drug elute morequickly than another solid or semi-solid drug, formation of the firstdrug to a dimension allowing substantial clearance between the drug andthe walls of the interior lumen may be desirable, as ocular fluidentering the implant contacts the drug over a greater surface area. Suchdrug dimensions are easily variable based on the elution and solubilitycharacteristics of a given drug. Conversely, initial drug elution may beslowed in embodiments with drugs dimensioned so that a minimal amount ofresidual space remains between the therapeutic agent and the walls ofthe interior lumen. In still other embodiments, the entirety of theimplant lumen is filled with a drug, to maximize either the duration ofdrug release or limit the need to recharge an implant.

Certain embodiments may comprise a shunt in addition to the drugdelivery portion of the implant. For example, once the implant ispositioned in the desired intraocular space (in an anterior-posteriordirection), a shunt portion of the implant comprising at least oneoutflow channel can be inserted into a physiological outflow space (forexample anchored to the trabecular meshwork and releasing fluid toSchlemm's canal). In some embodiments, a plurality of apertures thusassists in maintaining patency and operability of the drainage shuntportion of the implant. Moreover, as described above, a plurality ofapertures can assist in ameliorating any unwanted side effects involvingexcess fluid production or accumulation that may result from the actionsof the therapeutic agent delivered by the implant.

As described above, duration of drug release is desired over an extendedperiod of time. In some embodiments, an implant in accordance withembodiments described herein is capable of delivering a drug at acontrolled rate to a target tissue for a period of several (i.e. atleast three) months. In certain embodiments, implants can deliver drugsat a controlled rate to target tissues for about 6 months or longer,including 3, 4, 5, 6, 7, 8, 9, 12, 15, 18, and 24 months, withoutrequiring recharging. In still other embodiments, the duration ofcontrolled drug release (without recharging of the implant) exceeds 2years (e.g., 3, 4, 5, or more years). It shall be appreciated thatadditional time frames including ranges bordering, overlapping orinclusive of two or more of the values listed above are also used incertain embodiments.

In conjunction with the controlled release of a drug to a target tissue,certain doses of a drug (or drugs) are desirable over time, in certainembodiments. As such, in some embodiments, the total drug load, forexample the total load of a steroid, delivered to a target tissue overthe lifetime of an implant ranges from about 10 to about 1000 μg. Incertain embodiments the total drug load ranges from about 100 to about900 μg, from about 200 to about 800 μg, from about 300 to about 700 μg,or from about 400 to about 600 μg. In some embodiments, the total drugload ranges from about 10 to about 300 μg, from about 10 to about 500μg, or about 10 to about 700 μg. In other embodiments, total drug loadranges from about 200 to about 500 μg, from 400 to about 700 μg or fromabout 600 to about 1000 μg. In still other embodiments, total drug loadranges from about 200 to about 1000 μg, from about 400 to about 1000 μg,or from about 700 to about 1000 μg. In some embodiments total drug loadranges from about 500 to about 700 μg, about 550 to about 700 μg, orabout 550 to about 650 μg, including 575, 590, 600, 610, and 625 μg. Itshall be appreciated that additional ranges of drugs bordering,overlapping or inclusive of the ranges listed above are also used incertain embodiments.

Similarly, in other embodiments, controlled drug delivery is calculatedbased on the elution rate of the drug from the implant. In certain suchembodiments, an elution rate of a drug, for example, a steroid, is about0.05 μg/day to about 10 μg/day is achieved. In other embodiments anelution rate of about 0.05 μg/day to about 5 μg/day, about 0.05 μg/dayto about 3 μg/day, or about 0.05 μg/day to about 2 μg/day is achieved.In other embodiment, an elution rate of about 2 μg/day to about 5μg/day, about 4 μg/day to about 7 μg/day, or about 6 μg/day to about 10μg/day is achieved. In other embodiments, an elution rate of about 1μg/day to about 4 μg/day, about 3 μg/day to about 6 μg/day, or about 7μg/day to about 10 μg/day is achieved. In still other embodiments, anelution rate of about 0.05 μg/day to about 1 μg/day, including 0.06,0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 μg/dayis achieved. It shall be appreciated that additional ranges of drugsbordering, overlapping or inclusive of the ranges listed above are alsoused in certain embodiments.

Alternatively, or in addition to one or more of the parameters above,the release of drug from an implant may be controlled based on thedesired concentration of the drug at target tissues. In someembodiments, the desired concentration of a drug, for example, asteroid, at the target tissue, ranges from about 1 nM to about 100 nM.In other embodiments the desired concentration of a drug at the site ofaction ranges from about 10 nM to about 90 nM, from about 20 nM to about80 nM, from about 30 nM to about 70 nM, or from about 40 nM to about 60nM. In still other embodiments the desired concentration of a drug atthe site of action ranges from about 1 nM to about 40 nM, from about 20nM to about 60 nM, from about 50 nM to about 70 nM, or from about 60 nMto about 90 nM. In yet other embodiments the desired concentration of adrug at the site of action ranges from about 1 nM to about 30 nM, fromabout 10 nM to about 50 nM, from about 30 nM to about 70 nM, or fromabout 60 nM to about 100 nM. In some embodiments, the desiredconcentration of a drug at the site of action ranges from about 45 nM toabout 55 nM, including 46, 47, 48, 49, 50, 51, 52, 53, and 54 nM. Itshall be appreciated that additional ranges of drugs bordering,overlapping or inclusive of the ranges listed above are also used incertain embodiments.

Certain embodiments described above are rechargeable. In some suchembodiments, recharging is accomplished by injecting new drug into thelumen(s). In some embodiments, refilling the implanted drug deliveryimplant entails advancing a recharging device through the anteriorchamber to the proximal end of the implant where the clamping sleeve mayslide over the proximal end of the implant. See, e.g., FIG. 20A. Anoperator may then grasp the proximal end of the implant with theflexible clamping grippers to hold it securely. A new dose of drug in atherapeutic agent or a new drug is then pushed to its position withinthe implant by a flexible pusher tube which may be spring loaded. Insome embodiments, the pusher tube includes a small internal recess tosecurely hold the therapeutic agent while in preparation for delivery tothe implant. In other embodiments a flat surface propels the therapeuticagent into position within the implant.

The spring travel of the pusher is optionally pre-defined to push thetherapeutic agent a known distance to the distal-most portion of theinterior lumen of the implant. Alternatively, the spring travel can beset manually, for example if a new therapeutic agent is being placedprior to the time the resident therapeutic agent is fully eluted fromthe implant, thereby reducing the distance by which the new therapeuticagent needs to be advanced. In cooperation with optional anchorelements, the recharging process may be accomplished without significantdisplacement of the implant from its original position.

Optionally, seals for preventing leakage during recharging may beincluded in the recharging device. Such seals may desirable if, forexample, the form of the drug to be refilled is a liquid. Suitable sealsfor preventing leakage include, for example, an o-ring, a coating, ahydrophilic agent, a hydrophobic agent, and combinations thereof. Thecoating can be, for example, a silicone coat such as MDX™ siliconefluid.

In other embodiments, recharging entails the advancement of a rechargingdevice through the anterior chamber by way of a one-way valve. See FIGS.20B and 20C. The valve comprises two or more flaps 70, open at theproximal end and reversibly closed at the distal end. The advancement ofthe recharging device opens the flaps at the posterior end, which allowsfor the deposition of drug into the posterior chamber. Upon removal ofthe recharging device, the flaps return to their closed position (at thedistal end), thereby retaining the deposited drug within the lumen. Insome embodiments, the one way valve is formed such that a seal iscreated to prevent backflow of liquid (including powders or micropelletswith liquid-like flow properties) drug from the lumen. In otherembodiments, a fluid-tight seal is not formed.

Other suitable retention methods may be used to hold the newly placeddrug pellet in place. For example, in some embodiments, a deformableO-ring with an inner diameter smaller than the newly placed pellet isused. In such embodiments, the recharging device displaces the O-ringsufficiently to allow passage of the drug pellet through the O-ring.Upon removal of the device, however, the O-ring returns to its originaldiameter, thereby retaining the pellet within the lumen.

In yet other embodiments a plug made of a “self-healing” material thatis penetrable by the recharging device is used. In such embodiments,pressure from the recharging device allows the device to penetrate theplug and deposit a new drug into the interior lumen. Upon withdrawal ofthe recharging device, the plug re-seals, and retains the drug withinthe lumen.

The one-way valve may be created of any material sufficiently flexibleto allow the insertion and retention of a new drug into the lumen. Suchmaterials include, but are not limited to, silicone, Teflon®, flexiblegraphite, sponge, silicone rubber, silicone rubber with fiberglassreinforcement, Neoprene®, red rubber, wire inserted red rubber, cork &Neoprene®, vegetable fiber, cork & rubber, cork & nitrile, fiberglass,cloth inserted rubber, vinyl, nitrile, butyl, natural gum rubber,urethane, carbon fiber, fluoroelastomer, and the like.

Drugs

The therapeutic agents utilized with the drug delivery implant, mayinclude one or more drugs provided below, either alone or incombination. The drugs utilized may also be the equivalent of,derivatives of, or analogs of one or more of the drugs provided below.The drugs may include but are not limited to pharmaceutical agentsincluding anti-glaucoma medications, ocular agents, antimicrobial agents(e.g., antibiotic, antiviral, antiparasitic, antifungal agents),anti-inflammatory agents (including steroids or non-steroidalanti-inflammatory), biological agents including hormones, enzymes orenzyme-related components, antibodies or antibody-related components,oligonucleotides (including DNA, RNA, short-interfering RNA, antisenseoligonucleotides, and the like), DNA/RNA vectors, viruses (either wildtype or genetically modified) or viral vectors, peptides, proteins,enzymes, extracellular matrix components, and live cells configured toproduce one or more biological components. The use of any particulardrug is not limited to its primary effect or regulatory body-approvedtreatment indication or manner of use. Drugs also include compounds orother materials that reduce or treat one or more side effects of anotherdrug or therapeutic agent. As many drugs have more than a single mode ofaction, the listing of any particular drug within any one therapeuticclass below is only representative of one possible use of the drug andis not intended to limit the scope of its use with the ophthalmicimplant system.

As discussed above, the therapeutic agents may be combined with anynumber of excipients as is known in the art. In addition to thebiodegradable polymeric excipients discussed above, other excipients maybe used, including, but not limited to, benzyl alcohol, ethylcellulose,methylcellulose, hydroxymethylcellulose, cetyl alcohol, croscarmellosesodium, dextrans, dextrose, fructose, gelatin, glycerin, monoglycerides,diglycerides, kaolin, calcium chloride, lactose, lactose monohydrate,maltodextrins, polysorbates, pregelatinized starch, calcium stearate,magnesium stearate, silcon dioxide, cornstarch, talc, and the like. Theone or more excipients may be included in total amounts as low as about1%, 5%, or 10% and in other embodiments may be included in total amountsas high as 50%, 70% or 90%.

Examples of drugs may include various anti-secretory agents;antimitotics and other anti-proliferative agents, including amongothers, anti-angiogenesis agents such as angiostatin, anecortaveacetate, thrombospondin, VEGF receptor tyrosine kinase inhibitors andanti-vascular endothelial growth factor (anti-VEGF) drugs such asranibizumab (LUCENTIS®) and bevacizumab (AVASTIN®), pegaptanib(MACUGEN®), sunitinib and sorafenib and any of a variety of knownsmall-molecule and transcription inhibitors having anti-angiogenesiseffect; classes of known ophthalmic drugs, including: glaucoma agents,such as adrenergic antagonists, including for example, beta-blockeragents such as atenolol propranolol, metipranolol, betaxolol, carteolol,levobetaxolol, levobunolol and timolol; adrenergic agonists orsympathomimetic agents such as epinephrine, dipivefrin, clonidine,aparclonidine, and brimonidine; parasympathomimetics or cholingericagonists such as pilocarpine, carbachol, phospholine iodine, andphysostigmine, salicylate, acetylcholine chloride, eserine, diisopropylfluorophosphate, demecarium bromide); muscarinics; carbonic anhydraseinhibitor agents, including topical and/or systemic agents, for exampleacetozolamide, brinzolamide, dorzolamide and methazolamide,ethoxzolamide, diamox, and dichlorphenamide; mydriatic-cycloplegicagents such as atropine, cyclopentolate, succinylcholine, homatropine,phenylephrine, scopolamine and tropicamide; prostaglandins such asprostaglandin F2 alpha, antiprostaglandins, prostaglandin precursors, orprostaglandin analog agents such as bimatoprost, latanoprost, travoprostand unoprostone.

Other examples of drugs may also include anti-inflammatory agentsincluding for example glucocorticoids and corticosteroids such asbetamethasone, cortisone, dexamethasone, dexamethasone 21-phosphate,methylprednisolone, prednisolone 21-phosphate, prednisolone acetate,prednisolone, fluroometholone, loteprednol, medrysone, fluocinoloneacetonide, triamcinolone acetonide, triamcinolone, triamcinoloneacetonide, beclomethasone, budesonide, flunisolide, fluorometholone,fluticasone, hydrocortisone, hydrocortisone acetate, loteprednol,rimexolone and non-steroidal anti-inflammatory agents including, forexample, diclofenac, flurbiprofen, ibuprofen, bromfenac, nepafenac, andketorolac, salicylate, indomethacin, ibuprofen, naxopren, piroxicam andnabumetone; anti-infective or antimicrobial agents such as antibioticsincluding, for example, tetracycline, chlortetracycline, bacitracin,neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline,chloramphenicol, rifampicin, ciprofloxacin, tobramycin, gentamycin,erythromycin, penicillin, sulfonamides, sulfadiazine, sulfacetamide,sulfamethizole, sulfisoxazole, nitrofurazone, sodium propionate,aminoglycosides such as gentamicin and tobramycin; fluoroquinolones suchas ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, norfloxacin,ofloxacin; bacitracin, erythromycin, fusidic acid, neomycin, polymyxinB, gramicidin, trimethoprim and sulfacetamide; antifungals such asamphotericin B and miconazole; antivirals such as idoxuridinetrifluorothymidine, acyclovir, gancyclovir, interferon; antimicotics;immune-modulating agents such as antiallergenics, including, forexample, sodium chromoglycate, antazoline, methapyriline,chlorpheniramine, cetrizine, pyrilamine, prophenpyridamine;anti-histamine agents such as azelastine, emedastine and levocabastine;immunological drugs (such as vaccines and immune stimulants); MAST cellstabilizer agents such as cromolyn sodium, ketotifen, lodoxamide,nedocrimil, olopatadine and pemirolastciliary body ablative agents, suchas gentimicin and cidofovir and other ophthalmic agents such asverteporfin, proparacaine, tetracaine, cyclosporine and pilocarpine;inhibitors of cell-surface glycoprotein receptors; decongestants such asphenylephrine, naphazoline, tetrahydrazoline; lipids or hypotensivelipids; dopaminergic agonists and/or antagonists such as quinpirole,fenoldopam, and ibopamine; vasospasm inhibitors; vasodilators;antihypertensive agents; angiotensin converting enzyme (ACE) inhibitors;angiotensin-1 receptor antagonists such as olmesartan; microtubuleinhibitors; molecular motor (dynein and/or kinesin) inhibitors; actincytoskeleton regulatory agents such as cyctchalasin, latrunculin,swinholide A, ethacrynic acid, H-7, and Rho-kinase (ROCK) inhibitors;remodeling inhibitors; modulators of the extracellular matrix such astert-butylhydro-quinolone and AL-3037A; adenosine receptor agonistsand/or antagonists such as N-6-cylclophexyladenosine and(R)-phenylisopropyladenosine; serotonin agonists; hormonal agents suchas estrogens, estradiol, progestational hormones, progesterone, insulin,calcitonin, parathyroid hormone, peptide and vasopressin hypothalamusreleasing factor, growth factor antagonists or growth factors,including, for example, epidermal growth factor, fibroblast growthfactor, platelet derived growth factor or antagonists thereof (such asthose disclosed in U.S. Pat. No. 7,759,472 or U.S. patent applicationSer. Nos. 12/465,051, 12/564,863, or 12/641,270, each of which isincorporated in its entirety by reference herein), transforming growthfactor beta, somatotrapin, fibronectin, connective tissue growth factor,bone morphogenic proteins (BMPs); cytokines such as interleukins, CD44,cochlin, and serum amyloids, such as serum amyloid A.

Other therapeutic agents may include neuroprotective agents such aslubezole, nimodipine and related compounds, and including blood flowenhancers such as dorzolamide or betaxolol; compounds that promote bloodoxygenation such as erythropoeitin; sodium channels blockers; calciumchannel blockers such as nilvadipine or lomerizine; glutamate inhibitorssuch as memantine nitromemantine, riluzole, dextromethorphan oragmatine; acetylcholinsterase inhibitors such as galantamine;hydroxylamines or derivatives thereof, such as the water solublehydroxylamine derivative OT-440; synaptic modulators such as hydrogensulfide compounds containing flavonoid glycosides and/or terpenoids,such as Ginkgo biloba; neurotrophic factors such as glial cell-linederived neutrophic factor, brain derived neurotrophic factor; cytokinesof the IL-6 family of proteins such as ciliary neurotrophic factor orleukemia inhibitory factor; compounds or factors that affect nitricoxide levels, such as nitric oxide, nitroglycerin, or nitric oxidesynthase inhibitors; cannabinoid receptor agonsists such as WIN55-212-2;free radical scavengers such as methoxypolyethylene glycol thioester(MPDTE) or methoxypolyethlene glycol thiol coupled with EDTA methyltriester (MPSEDE); anti-oxidants such as astaxathin, dithiolethione,vitamin E, or metallocorroles (e.g., iron, manganese or galliumcorroles); compounds or factors involved in oxygen homeostasis such asneuroglobin or cytoglobin; inhibitors or factors that impactmitochondrial division or fission, such as Mdivi-1 (a selectiveinhibitor of dynamin related protein 1 (Drp1)); kinase inhibitors ormodulators such as the Rho-kinase inhibitor H-1152 or the tyrosinekinase inhibitor AG1478; compounds or factors that affect integrinfunction, such as the Beta 1-integrin activating antibody HUTS-21;N-acyl-ethanaolamines and their precursors, N-acyl-ethanolaminephospholipids; stimulators of glucagon-like peptide 1 receptors (e.g.,glucagon-like peptide 1); polyphenol containing compounds such asresveratrol; chelating compounds; apoptosis-related protease inhibitors;compounds that reduce new protein synthesis; radiotherapeutic agents;photodynamic therapy agents; gene therapy agents; genetic modulators;auto-immune modulators that prevent damage to nerves or portions ofnerves (e.g., demyelination) such as glatimir; myelin inhibitors such asanti-NgR Blocking Protein, NgR(310)ecto-Fc; other immune modulators suchas FK506 binding proteins (e.g., FKBP51); and dry eye medications suchas cyclosporine A, delmulcents, and sodium hyaluronate.

Other therapeutic agents that may be used include: other beta-blockeragents such as acebutolol, atenolol, bisoprolol, carvedilol, asmolol,labetalol, nadolol, penbutolol, and pindolol; other corticosteroidal andnon-steroidal anti-inflammatory agents such aspirin, betamethasone,cortisone, diflunisal, etodolac, fenoprofen, fludrocortisone,flurbipofen, hydrocortisone, ibuprofen, indomethacine, ketoprofen,meclofenamate, mefenamic acid, meloxicam, methylprednisolone,nabumetone, naproxen, oxaprozin, prednisolone, prioxicam, salsalate,sulindac and tolmetin; COX-2 inhibitors like celecoxib, rofecoxib and.Valdecoxib; other immune-modulating agents such as aldesleukin,adalimumab (HUMIRA®), azathioprine, basiliximab, daclizumab, etanercept(ENBREL®), hydroxychloroquine, infliximab (REMICADE®), leflunomide,methotrexate, mycophenolate mofetil, and sulfasalazine; otheranti-histamine agents such as loratadine, desloratadine, cetirizine,diphenhydramine, chlorpheniramine, dexchlorpheniramine, clemastine,cyproheptadine, fexofenadine, hydroxyzine and promethazine; otheranti-infective agents such as aminoglycosides such as amikacin andstreptomycin; anti-fungal agents such as amphotericin B, caspofungin,clotrimazole, fluconazole, itraconazole, ketoconazole, voriconazole,terbinafine and nystatin; anti-malarial agents such as chloroquine,atovaquone, mefloquine, primaquine, quinidine and quinine:anti-mycobacterium agents such as ethambutol, isoniazid, pyrazinamide,rifampin and rifabutin; anti-parasitic agents such as albendazole,mebendazole, thiobendazole, metronidazole, pyrantel, atovaquone,iodoquinaol, ivermectin, paromycin, praziquantel, and trimatrexate;other anti-viral agents, including anti-CMV or anti-herpetic agents suchas acyclovir, cidofovir, famciclovir, gangciclovir, valacyclovir,valganciclovir, vidarabine, trifluridine and foscarnet; proteaseinhibitors such as ritonavir, saquinavir, lopinavir, indinavir,atazanavir, amprenavir and nelfinavir;nucleotide/nucleoside/non-nucleoside reverse transcriptase inhibitorssuch as abacavir, ddI, 3TC, d4T, ddC, tenofovir and emtricitabine,delavirdine, efavirenz and nevirapine; other anti-viral agents such asinterferons, ribavirin and trifluridiene; other anti-bacterial agents,including cabapenems like ertapenem, imipenem and meropenem;cephalosporins such as cefadroxil, cefazolin, cefdinir, cefditoren,cephalexin, cefaclor, cefepime, cefoperazone, cefotaxime, cefotetan,cefoxitin, cefpodoxine, cefprozil, ceftaxidime, ceftibuten, ceftizoxime,ceftriaxone, cefuroxime and loracarbef; other macrolides and ketolidessuch as azithromycin, clarithromycin, dirithromycin and telithromycin:penicillins (with and without clavulanate) including amoxicillin,ampicillin, pivampicillin, dicloxacillin, nafcillin, oxacillin,piperacillin, and ticarcillin; tetracyclines such as doxycycline,minocycline and tetracycline; other anti-bacterials such as aztreonam,chloramphenicol, clindamycin, linezolid, nitrofurantoin and vancomycin;alpha blocker agents such as doxazosin, prazosin and terazosin;calcium-channel blockers such as amlodipine, bepridil, diltiazem,felodipine, isradipine, nicardipine, nifedipine, nisoldipine andverapamil; other anti-hypertensive agents such as clonidine, diazoxide,fenoldopan, hydralazine, minoxidil, nitroprusside, phenoxybenzamine,epoprostenol, tolazoline, treprostinil and nitrate-based agents;anti-coagulant agents, including heparins and heparinoids such asheparin, dalteparin, enoxaparin, tinzaparin and fondaparinux; otheranti-coagulant agents such as hirudin, aprotinin, argatroban,bivalirudin, desirudin, lepirudin, warfarin and ximelagatran;anti-platelet agents such as abciximab, clopidogrel, dipyridamole,optifibatide, ticlopidine and tirofiban; prostaglandin PDE-5 inhibitorsand other prostaglandin agents such as alprostadil, carboprost,sildenafil, tadalafil and vardenafil; thrombin inhibitors;antithrombogenic agents; anti-platelet aggregating agents; thrombolyticagents and/or fibrinolytic agents such as alteplase, anistreplase,reteplase, streptokinase, tenecteplase and urokinase; anti-proliferativeagents such as sirolimus, tacrolimus, everolimus, zotarolimus,paclitaxel and mycophenolic acid; hormonal-related agents includinglevothyroxine, fluoxymestrone, methyltestosterone, nandrolone,oxandrolone, testosterone, estradiol, estrone, estropipate, clomiphene,gonadotropins, hydroxyprogesterone, levonorgestrel, medroxyprogesterone,megestrol, mifepristone, norethindrone, oxytocin, progesterone,raloxifene and tamoxifen; anti-neoplastic agents, including alkylatingagents such as carmustine lomustine, melphalan, cisplatin,fluorouracil3, and procarbazine antibiotic-like agents such asbleomycin, daunorubicin, doxorubicin, idarubicin, mitomycin andplicamycin; anti proliferative agents (such as 1,3-cis retinoic acid,5-fluorouracil, taxol, rapamycin, mitomycin C and cisplatin);antimetabolite agents such as cytarabine, fludarabine, hydroxyurea,mercaptopurine and 5-fluorouracil (5-FJ): immune modulating agents suchas aldesleukin, imatinib, rituximab and tositumomab; mitotic inhibitorsdocetaxel, etoposide, vinblastine and vincristine; radioactive agentssuch as strontium-89; and other anti-neoplastic agents such asirinotecan, topotecan and mitotane.

While certain embodiments of the disclosure have been described, theseembodiments have been presented by way of example only, and are notintended to limit the scope of the disclosure. Indeed, the novelmethods, systems, and devices described herein may be embodied in avariety of other forms. For example, embodiments of one illustrated ordescribed implant may be combined with embodiments of anotherillustrated or described shunt. Moreover, the implants described abovemay be utilized for other purposes. For example, the implants may beused to drain fluid from the anterior chamber to other locations of theeye or outside the eye. Furthermore, various omissions, substitutionsand changes in the form of the methods, systems, and devices describedherein may be made without departing from the spirit of the disclosure.

1.-36. (canceled)
 37. A system for administering a therapeutic agent toan damaged or diseased eye, comprising: an ocular implant deliveryapparatus comprising: a proximal end; a distal end; an ocular implantcomprising: an elongate outer shell having a proximal end, a distal end,said outer shell being shaped to define an interior lumen, wherein saidinterior lumen is suitable for receiving one or more micro-tablets,wherein said outer shell comprises a first thickness, wherein said outershell comprises one or more regions of drug release; and a therapeuticagent formed in at least one micro-tablet; and wherein each micro-tablethas a density of about 0.7 g/cc to about 1.6 g/cc.
 38. The system ofclaim 37, wherein said micro-tablets have an aspect ratio of length todiameter of about 2.8 to 3.6.
 39. A method for the intravitrealinjection of an agent for the treatment of an ocular disorder,comprising: advancing to the surface of the sclera of an eye a deliveryapparatus comprising: a proximal end; a distal end; a cannula containingone or more micro-tablets, wherein said micro-tablets have a density ofabout 0.7 g/cc to about 1.6 g/cc; and an activator that functions toexpel the contents of said cannula from said apparatus via passagethrough said proximal end; piercing said scleral surface to create ahole in said sclera; further advancing said delivery apparatus thru saidhole such that said proximal end is within the vitreal cavity of saideye; activating said activator to expel said micro-tablets; andwithdrawing said apparatus from said eye, thereby treating said disorderby the delivery of said micro-tablets.
 40. The method of claim 39,wherein said piercing of said sclera is performed using an apparatushave a sharpened proximal end.
 41. The method of claim 39, wherein saidhole within said sclera is sufficiently small to be self-healing. 42.The method of claim 37, wherein the ocular implant delivery apparatusfurther comprises a cannula having an inner diameter of about 23 to 25gauge.
 43. The method of claim 37, wherein the one or more regions ofdrug release comprise one or more orifices.
 44. The method of claim 43,wherein the at least one of the one or more orifices comprises ahydrogel plug in or adjacent to the orifice.
 45. The method of claim 44,wherein the therapeutic agent passes through the hydrogel plug as itelutes from the implant the hydrogel plug thereby at least in partdefining an elution rate of the therapeutic agent from the ocularimplant.
 46. The method of claim 37, wherein said micro-tablets have aminor axis of about 0.28 to 0.31 mm and a major axis of about 0.8 to 1.1mm.
 47. The method of claim 37, said therapeutic agent havinganti-vascular endothelial growth factor (VEGF) effects, wherein saidanti-VEGF agent is lyophilized prior to formation of the micro-tablets.48. The method of claim 47, wherein said anti-VEGF agent comprises atleast 70% by weight of the total weight of each micro-tablet.
 49. Themethod of claim 37, wherein said micro-tablets have a surface area tovolume ratio of about 13 to
 17. 50. The method of claim 37, wherein saidmicro-tablets are configured to balance osmotic pressure between saidinterior lumen and an ocular environment external to an implant afterimplantation.
 51. The method of claim 37, wherein said micro-tablets arecoated with a polymeric coating that regulates the release of saidtherapeutic agent from said micro-tablet.
 52. The method of claim 37,wherein said first therapeutic agent is an anti-angiogenesis agentselected from the group consisting of angiostatin, anecortave acetate,thrombospondin, VEGF receptor tyrosine kinase inhibitors andanti-vascular endothelial growth factor (anti-VEGF) drugs.
 53. Themethod of claim 52, wherein said anti-VEGF drugs are selected from thegroup consisting of ranibizumab, bevacizumab, pegaptanib, sunitinib andsorafenib.
 54. The method of claim 39, wherein the cannula comprises aninner diameter of about 23 to 25 gauge.
 55. The method of claim 39,wherein the one or more micro-tablets comprise a therapeutic agenthaving anti-vascular endothelial growth factor (VEGF) effects.
 56. Themethod of claim 39, wherein said micro-tablets have a minor axis ofabout 0.28 to 0.31 mm and a major axis of about 0.8 to 1.1 mm.